Novel human proteases and polynucleotides encoding the same

ABSTRACT

Novel human polynucleotide and polypeptide sequences are disclosed that can be used in therapeutic, diagnostic, and pharmacogenomic applications.

[0001] The present application claims the benefit of U.S. ProvisionalApplication No. 60/181,924 which was filed on Feb. 11, 2000 and isherein incorporated by reference in its entirety.

1. INTRODUCTION

[0002] The present invention relates to the discovery, identification,and characterization of novel human polynucleotides encoding proteinssharing sequence similarity with mammalian proteases. The inventionencompasses the described polynucleotides, host cell expression systems,the encoded proteins, fusion proteins, polypeptides and peptides,antibodies to the encoded proteins and peptides, and geneticallyengineered animals that either lack or over express the disclosedsequences, antagonists and agonists of the proteins, and other compoundsthat modulate the expression or activity of the proteins encoded by thedisclosed polynucleotides that can be used for diagnosis, drugscreening, clinical trial monitoring, the treatment of physiologicaldisorders or infectious disease.

2. BACKGROUND OF THE INVENTION

[0003] Proteases cleave protein substrates as part of degradation,maturation, and secretary pathways within the body. Proteases have beenassociated with, inter alia, regulating development, diabetes, obesity,infertility, modulating cellular processes, and infectious disease.

3. SUMMARY OF THE INVENTION

[0004] The present invention relates to the discovery, identification,and characterization of nucleotides that encode novel human proteins andthe corresponding amino acid sequences of these proteins. The novelhuman proteins (NHPs) described for the first time herein sharestructural similarity with animal proteases, and particularlyaminopeptidases.

[0005] The novel human nucleic acid (cDNA) sequences described herein,encode proteins/open reading frames (ORFs) of 507, 69, 290, 265, 211,267, 186, 242, 453, 532, 428, 509, and 484 amino acids in length (seeSEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26respectively).

[0006] The invention also encompasses agonists and antagonists of thedescribed NHPs, including small molecules, large molecules, mutant NHPs,or portions thereof that compete with native NHPs, NHP peptides, and NHPantibodies, as well as nucleotide sequences that can be used to inhibitthe expression of the described NHPs (e.g., antisense and ribozymemolecules, and gene or regulatory sequence replacement constructs) or toenhance the expression of the described NHPs (e.g., expressionconstructs that place the described sequence under the control of astrong promoter system), and transgenic animals that express a NHPtransgene, or “knockout” animals (which can be conditional) that do notexpress a functional NHP. A gene trapped “knockout” murine ES cell linehas been produced that mutates a murine homolog of the described NHPs.Accordingly, an additional aspect of the present invention includes aknockout mouse that is characterized by reduced levels of NHPexpression.

[0007] Further, the present invention also relates to processes foridentifying compounds that modulate, i.e., act as agonists orantagonists, of NHP expression and/or NHP activity that utilize purifiedpreparations of the described NHP and/or NHP product, or cellsexpressing the same. Such compounds can be used as therapeutic agentsfor the treatment of any of a wide variety of symptoms associated withbiological disorders or imbalances.

4. DESCRIPTION OF THE SEQUENCE LISTING AND FIGURES

[0008] The Sequence Listing provides the sequences of the NHP ORFsencoding the described NHP amino acid sequences. SEQ ID NO:27 describesa NHP ORF with flanking sequences.

5. DETAILED DESCRIPTION OF THE INVENTION

[0009] The NHPs, described for the first time herein, are novel proteinsthat are expressed in, inter alia, human cell lines, and human fetalbrain, brain, pituitary, cerebellum, spinal cord, thymus, spleen, lymphnode, bone marrow, trachea, kidney, fetal liver, liver, prostate,testis, thyroid, adrenal gland, pancreas, salivary gland, stomach, smallintestine, colon, uterus, placenta, mammary gland, adipose, skin,esophagus, bladder, cervix, rectum, pericardium, hypothalamus, ovary,fetal kidney, and fetal lung cells.

[0010] The described NHPs share sequence similarity withaminopeptidases, and particularly aminopeptidase P, from a variety oforganisms. Aminopeptidases have been implicated in a variety cellularand disease processes and have been subject to considerable scientificscrutiny. For example, U.S. Pat. No. 5,972,680 describes uses andapplications for proteases such as the presently described NHPs and U.S.Pat. No. 5,656,603 describes a variety of chemical antagonists ofaminopeptidase P, both of which are herein incorporated by reference intheir entirety.

[0011] The described sequences were compiled from gene trapped cDNAs andclones isolated from a human testis cDNA library (Edge Biosystems,Gaithersburg, Md.). The present invention encompasses the nucleotidespresented in the Sequence Listing, host cells expressing suchnucleotides, the expression products of such nucleotides, and: (a)nucleotides that encode mammalian homologs of the described sequences,including the specifically described NHPs, and the NHP products; (b)nucleotides that encode one or more portions of a NHP that correspond tofunctional domains of the NHP, and the polypeptide products specified bysuch nucleotide sequences, including but not limited to the novelregions of any active domain(s); (c) isolated nucleotides that encodemutant versions, engineered or naturally occurring, of a described NHPin which all or a part of at least one domain is deleted or altered, andthe polypeptide products specified by such nucleotide sequences,including but not limited to soluble proteins and peptides in which allor a portion of the signal sequence is deleted; (d) nucleotides thatencode chimeric fusion proteins containing all or a portion of a codingregion of a NHP, or one of its domains (e.g., a receptor or ligandbinding domain, accessory protein/self-association domain, etc.) fusedto another peptide or polypeptide; or (e) therapeutic or diagnosticderivatives of the described polynucleotides such as oligonucleotides,antisense polynucleotides, ribozymes, dsRNA, or gene therapy constructscomprising a sequence first disclosed in the Sequence Listing.

[0012] As discussed above, the present invention includes: (a) the humanDNA sequences presented in the Sequence Listing (and vectors comprisingthe same) and additionally contemplates any nucleotide sequence encodinga contiguous NHP open reading frame (ORF), or a contiguous exon splicejunction first described in the Sequence Listing, that hybridizes to acomplement of a DNA sequence presented in the Sequence Listing underhighly stringent conditions, e.g., hybridization to filter-bound DNA in0.5 M NaHPO₄, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65° C., andwashing in 0.1SSC/0.1% SDS at 68° C. (Ausubel F. M. et al., eds. 1989,Current Protocols in Molecular Biology, Vol. I, Green PublishingAssociates, Inc., and John Wiley & sons, Inc., New York, at p. 2.10.3)and encodes a functionally equivalent gene product. Additionallycontemplated are any nucleotide sequences that hybridize to thecomplement of the DNA sequence that encode and express an amino acidsequence presented in the Sequence Listing under moderately stringentconditions, e.g., washing in 0.2×SSC/0.1% SDS at 42° C. (Ausubel et al.,1989, supra), yet still encode a functionally equivalent NHP product.Functional equivalents of a NHP include naturally occurring NHPs presentin other species and mutant NHPs whether naturally occurring orengineered (by site directed mutagenesis, gene shuffling, directedevolution as described in, for example, U.S. Pat. No. 5,837,458). Theinvention also includes degenerate nucleic acid variants of thedisclosed NHP polynucleotide sequences.

[0013] Additionally contemplated are polynucleotides encoding a NHP ORF,or its functional equivalent, encoded by a polynucleotide sequence thatis about 99, 95, 90, or about 85 percent similar or identical tocorresponding regions of the nucleotide sequences of the SequenceListing (as measured by BLAST sequence comparison analysis using, forexample, the GCG sequence analysis package using standard defaultsettings).

[0014] The invention also includes nucleic acid molecules, preferablyDNA molecules, that hybridize to, and are therefore the complements of,the described NHP nucleotide sequences. Such hybridization conditionsmay be highly stringent or less highly stringent, as described above. Ininstances where the nucleic acid molecules are deoxyoligonucleotides(“DNA oligos”), such molecules are generally about 16 to about 100 baseslong, or about 20 to about 80, or about 34 to about 45 bases long, orany variation or combination of sizes represented therein thatincorporate a contiguous region of sequence first disclosed in theSequence Listing. Such oligonucleotides can be used in conjunction withthe polymerase chain reaction (PCR) to screen libraries, isolate clones,and prepare cloning and sequencing templates, etc.

[0015] Alternatively, such NHP oligonucleotides can be used ashybridization probes for screening libraries, and assessing geneexpression patterns (particularly using a micro array or high-throughput“chip” format). Additionally, a series of the described NHPoligonucleotide sequences, or the complements thereof, can be used torepresent all or a portion of the described NHP sequences. Anoligonucleotide or polynucleotide sequence first disclosed in at least aportion of one or more of the sequences of SEQ ID NOS: 1-27 can be usedas a hybridization probe in conjunction with a solid supportmatrix/substrate (resins, beads, membranes, plastics, polymers, metal ormetallized substrates, crystalline or polycrystalline substrates, etc.).Of particular note are spatially addressable arrays (i.e., gene chips,microtiter plates, etc.) of oligonucleotides and polynucleotides, orcorresponding oligopeptides and polypeptides, wherein at least one ofthe biopolymers present on the spatially addressable array comprises anoligonucleotide or polynucleotide sequence first disclosed in at leastone of the sequences of SEQ ID NOS: 1-27, or an amino acid sequenceencoded thereby. Methods for attaching biopolymers to, or synthesizingbiopolymers on, solid support matrices, and conducting binding studiesthereon are disclosed in, inter alia, U.S. Pat. Nos. 5,700,637,5,556,752, 5,744,305, 4,631,211, 5,445,934, 5,252,743, 4,713,326,5,424,186, and 4,689,405 the disclosures of which are hereinincorporated by reference in their entirety.

[0016] Addressable arrays-comprising sequences first disclosed in SEQ IDNOS:1-27 can be used to identify and characterize the temporal andtissue specific expression of a gene. These addressable arraysincorporate oligonucleotide sequences of sufficient length to confer therequired specificity, yet be within the limitations of the productiontechnology. The length of these probes is within a range of betweenabout 8 to about 2000 nucleotides. Preferably the probes consist of 60nucleotides and more preferably 25 nucleotides from the sequences firstdisclosed in SEQ ID NOS:1-27.

[0017] For example, a series of the described oligonucleotide sequences,or the complements thereof, can be used in chip format to represent allor a portion of the described sequences. The oligonucleotides, typicallybetween about 16 to about 40 (or any whole number within the statedrange) nucleotides in length can partially overlap each other and/or thesequence may be represented using oligonucleotides that do not overlap.Accordingly, the described polynucleotide sequences shall typicallycomprise at least about two or three distinct oligonucleotide sequencesof at least about 8 nucleotides in length that are each first disclosedin the described Sequence Listing. Such oligonucleotide sequences canbegin at any nucleotide present within a sequence in the SequenceListing and proceed in either a sense (5′-to-3′) orientation vis-a-visthe described sequence or in an antisense orientation.

[0018] Microarray-based analysis allows the discovery of broad patternsof genetic activity, providing new understanding of gene functions andgenerating novel and unexpected insight into transcriptional processesand biological mechanisms. The use of addressable arrays comprisingsequences first disclosed in SEQ ID NOS:1-27 provides detailedinformation about transcriptional changes involved in a specificpathway, potentially leading to the identification of novel componentsor gene functions that manifest themselves as novel phenotypes.

[0019] Probes consisting of sequences first disclosed in SEQ ID NOS:1-27can also be used in the identification, selection and validation ofnovel molecular targets for drug discovery. The use of these uniquesequences permits the direct confirmation of drug targets andrecognition of drug dependent changes in gene expression that aremodulated through pathways distinct from the drugs intended target.These unique sequences therefore also have utility in defining andmonitoring both drug action and toxicity.

[0020] As an example of utility, the sequences first disclosed in SEQ IDNOS:1-27 can be utilized in microarrays or other assay formats, toscreen collections of genetic material from patients who have aparticular medical condition. These investigations can also be carriedout using the sequences first disclosed in SEQ ID. NOS:1-27 in silicoand by comparing previously collected genetic databases and thedisclosed sequences using computer software known to those in the art.

[0021] Thus the sequences first disclosed in SEQ ID NOS:1-27 can be usedto identify mutations associated with a particular disease and also as adiagnostic or prognostic assay.

[0022] Although the presently described sequences have been specificallydescribed using nucleotide sequence, it should be appreciated that eachof the sequences can uniquely be described using any of a wide varietyof additional structural attributes, or combinations thereof. Forexample, a given sequence can be described by the net composition of thenucleotides present within a given region of the sequence in conjunctionwith the presence of one or more specific oligonucleotide sequence(s)first disclosed in the SEQ ID NOS: 1-27. Alternatively, a restrictionmap specifying the relative positions of restriction endonucleasedigestion sites, or various palindromic or other specificoligonucleotide sequences can be used to structurally describe a givensequence. Such restriction maps, which are typically generated by widelyavailable computer programs (e.g., the University of Wisconsin GCGsequence analysis package, SEQUENCHER 3.0, Gene Codes Corp., Ann Arbor,Mich., etc.), can optionally be used in conjunction with one or morediscrete nucleotide sequence(s) present in the sequence that can bedescribed by the relative position of the sequence relative to one ormore additional sequence(s) or one or more restriction sites present inthe disclosed sequence.

[0023] For oligonucleotide probes, highly stringent conditions mayrefer, e.g., to washing in 6×SSC/0.05% sodium pyrophosphate at 37° C.(for 14-base oligos), 48° C. (for 17-base oligos), 55° C. (for 20-baseoligos), and 60° C. (for 23-base oligos). These nucleic acid moleculesmay encode or act as NHP gene antisense molecules, useful, for example,in NHP gene regulation (for and/or as antisense primers in amplificationreactions of NHP nucleic acid sequences). With respect to NHP generegulation, such techniques can be used to regulate biologicalfunctions. Further, such sequences may be used as part of ribozymeand/or triple helix sequences that are also useful for NHP generegulation.

[0024] Inhibitory antisense or double stranded oligonucleotides canadditionally comprise at least one modified base moiety which isselected from the group including but not limited to 5-fluorouracil,5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine,4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w,and 2, 6-diaminopurine.

[0025] The antisense oligonucleotide can also comprise at least onemodified sugar moiety selected from the group including but not limitedto arabinose, 2-fluoroarabinose, xylulose, and hexose.

[0026] In yet another embodiment, the antisense oligonucleotide willcomprise at least one modified phosphate backbone selected from thegroup consisting of a phosphorothioate, a phosphorodithioate, aphosphoramidothioate, a phosphoramidate, a phosphordiamidate, amethylphosphonate, an alkyl phosphotriester, and a formacetal or analogthereof.

[0027] In yet another embodiment, the antisense oligonucleotide is anα-anomeric oligonucleotide. An α-anomeric oligonucleotide forms specificdouble-stranded hybrids with complementary RNA in which, contrary to theusual β-units, the strands run parallel to each other (Gautier et al.,1987, Nucl. Acids Res. 15:6625-6641). The oligonucleotide is a2′-O-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res.15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBSLett. 215:327-330). Alternatively, double stranded RNA can be used todisrupt the expression and function of a targeted NHP.

[0028] Oligonucleotides of the invention can be synthesized by standardmethods known in the art, e.g. by use of an automated DNA synthesizer(such as are commercially available from Biosearch, Applied Biosystems,etc.). As examples, phosphorothioate oligonucleotides can be synthesizedby the method of Stein et al. (1988, Nucl. Acids Res. 16:3209), andmethylphosphonate oligonucleotides can be prepared by use of controlledpore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci.U.S.A. 85:7448-7451), etc.

[0029] Low stringency conditions are well known to those of skill in theart, and will vary predictably depending on the specific organisms fromwhich the library and the labeled sequences are derived. For guidanceregarding such conditions see, for example, Sambrook et al., 1989,Molecular Cloning, A Laboratory Manual (and periodic updates thereof),Cold Springs Harbor Press, N.Y.; and Ausubel et al., 1989, CurrentProtocols in Molecular Biology, Green Publishing Associates and WileyInterscience, N.Y.

[0030] Alternatively, suitably labeled NHP nucleotide probes can be usedto screen a human genomic library using appropriately stringentconditions or by PCR. The identification and characterization of humangenomic clones is helpful for identifying polymorphisms (including, butnot limited to, nucleotide repeats, microsatellite alleles, singlenucleotide polymorphisms, or coding single nucleotide polymorphisms),determining the genomic structure of a given locus/allele, and designingdiagnostic tests. For example, sequences derived from regions adjacentto the intron/exon boundaries of the human gene can be used to designprimers for use in amplification assays to detect mutations within theexons, introns, splice sites (e.g., splice acceptor and/or donor sites),etc., that can be used in diagnostics and pharmacogenomics.

[0031] Further, a NHP homolog can be isolated from nucleic acid from anorganism of interest by performing PCR using two degenerate or “wobble”oligonucleotide primer pools designed on the basis of amino acidsequences within the NHP products disclosed herein. The template for thereaction may be total RNA, mRNA, and/or cDNA obtained by reversetranscription of mRNA prepared from human or non-human cell linesor-tissue known or suspected to express an allele of a NHP gene.

[0032] The PCR product can be subcloned and sequenced to ensure that theamplified sequences represent the sequence of the desired NHP gene. ThePCR fragment can then be used to isolate a full length cDNA clone by avariety of methods. For example, the amplified fragment can be labeledand used to screen a cDNA library, such as a bacteriophage cDNA library.Alternatively, the labeled fragment can be used to isolate genomicclones via the screening of a genomic library.

[0033] PCR technology can also be used to isolate full length cDNAsequences. For example, RNA can be isolated,.following standardprocedures, from an appropriate cellular or tissue source (i.e., oneknown, or suspected, to express a NHP gene). A reverse transcription(RT) reaction can be performed on the RNA using an oligonucleotideprimer specific for the most 5′ end of the amplified fragment for thepriming of first strand synthesis. The resulting RNA/DNA hybrid may thenbe “tailed” using a standard terminal transferase reaction, the hybridmay be digested with RNase H, and second strand synthesis may then beprimed with a complementary primer. Thus, cDNA sequences upstream of theamplified fragment can be isolated. For a review of cloning strategiesthat can be used, see e.g., Sambrook et al., 1989, supra.

[0034] A cDNA encoding a mutant NHP gene can be isolated, for example,by using PCR. In this case, the first cDNA strand may be synthesized byhybridizing an oligo-dT oligqnucleotide to mRNA isolated from tissueknown or suspected to be expressed in an individual putatively carryinga mutant NHP allele, and by extending the new strand with reversetranscriptase. The second strand of the cDNA is then synthesized usingan oligonucleotide that hybridizes specifically to the 5′ end of thenormal gene. Using these two primers, the product is then amplified viaPCR, optionally cloned into a suitable vector, and subjected to DNAsequence analysis through methods well known to those of skill in theart. By comparing the DNA sequence of the mutant NHP allele to that of acorresponding normal NHP allele, the mutation(s) responsible for theloss or alteration of function of the mutant NHP gene product can beascertained.

[0035] Alternatively, a genomic library can be constructed using DNAobtained from an individual suspected of or known to carry a mutant NHPallele (e.g., a person manifesting a NHP-associated phenotype such as,for example, obesity, high blood pressure, connective tissue disorders,infertility, etc.), or a cDNA library can be constructed using RNA froma tissue known, or suspected, to express a mutant NHP allele. A normalNHP gene, or any suitable fragment thereof, can then be labeled and usedas a probe to identify the corresponding mutant NHP allele in suchlibraries. Clones containing mutant NHP gene sequences can then bepurified and subjected to sequence analysis according to methods wellknown to those skilled in the art.

[0036] Additionally, an expression library can be constructed utilizingcDNA synthesized from, for example, RNA isolated from a tissue known, orsuspected, to express a mutant NHP allele in an individual suspected ofor known to carry such a mutant allele. In this manner, gene productsmade by the putatively mutant tissue can be expressed and screened usingstandard antibody screening techniques in conjunction with antibodiesraised against normal NHP product, as described below. (For screeningtechniques, see, for example, Harlow, E. and Lane, eds., 1988,“Antibodies: A Laboratory Manual”, Cold Spring Harbor Press, Cold SpringHarbor.)

[0037] Additionally, screening can be accomplished by screening withlabeled NHP fusion proteins, such as, for example, alkalinephosphatase-NHP or NHP-alkaline phosphatase fusion proteins. In caseswhere a NHP mutation results in an expressed gene product with alteredfunction (e.g., as a result of a missense or a frameshift mutation),polyclonal antibodies to NHP are likely to cross-react with acorresponding mutant NHP gene product. Library clones detected via theirreaction with such labeled antibodies can be purified and subjected tosequence analysis according to methods well known in the art.

[0038] The invention also encompasses (a) DNA vectors that contain anyof the foregoing NHP coding sequences and/or their complements (i.e.,antisense); (b) DNA expression vectors that contain any of the foregoingNHP coding sequences operatively associated with a regulatory elementthat directs the expression of the coding sequences (for example, baculovirus as described in U.S. Pat. No. 5,869,336 herein incorporated byreference); (c) genetically engineered host cells that contain any ofthe foregoing NHP coding sequences operatively associated with aregulatory element that directs the expression of the coding sequencesin the host cell; and (d) genetically engineered host cells that expressan endogenous NHP gene under the control of an exogenously introducedregulatory element (i.e., gene activation). As used herein, regulatoryelements include, but are not limited to, inducible and non-induciblepromoters, enhancers, operators and other elements known to thoseskilled in the art that drive and regulate expression. Such regulatoryelements include but are not limited to the cytomegalovirus (hCMV)immediate early gene, regulatable, viral elements (particularlyretroviral LTR promoters), the early or late promoters of SV40adenovirus, the lac system, the trp system, the TAC system, the TRCsystem, the major operator and promoter regions of phage lambda, thecontrol regions of fd coat protein, the promoter for 3-phosphoglyceratekinase (PGK), the promoters of acid phosphatase, and the promoters ofthe yeast α-mating factors.

[0039] The present invention also encompasses antibodies andanti-idiotypic antibodies (including Fab fragments), antagonists andagonists of a NHP, as well as compounds or nucleotide constructs thatinhibit expression of a NHP gene (transcription factor inhibitors,antisense and ribozyme molecules, or gene or regulatory sequencereplacement constructs), or promote the expression of a NHP (e.g.,expression constructs in which NHP coding sequences are operativelyassociated with expression control elements such as promoters,promoter/enhancers, etc.).

[0040] The NHPs or NHP peptides, NHP fusion proteins, NHP nucleotidesequences, antibodies, antagonists and agonists can be useful for thedetection of mutant NHPs or inappropriately expressed NHPs for thediagnosis of disease. The NHP proteins or peptides, NHP fusion proteins,NHP nucleotide sequences, host cell expression systems, antibodies,antagonists, agonists and genetically engineered cells and animals canbe used for screening for drugs (or high throughput screening ofcombinatorial libraries) effective in the treatment of the symptomaticor phenotypic manifestations of perturbing the normal function of a NHPin the body. The use of engineered host cells and/or animals may offeran advantage in that such systems allow not only for the identificationof compounds that bind to the endogenous receptor for a NHP, but canalso identify compounds that trigger NHP-mediated activities orpathways.

[0041] Finally, the NHP products can be used as therapeutics. Forexample, soluble derivatives such as NHP peptides/domains correspondingto NHP, NHP fusion protein products (especially NHP-Ig fusion proteins,i.e., fusions of a NHP, or a domain of a NHP, to an IgFc), NHPantibodies and anti-idiotypic antibodies (including Fab fragments),antagonists or agonists (including compounds that modulate or act ondownstream targets in a. NHP-mediated pathway) can be used to directlytreat diseases or disorders. For instance, the administration of aneffective amount of soluble NHP, or a NHP-IgFc fusion protein or ananti-idiotypic antibody (or its Fab) that mimics the NHP could activateor effectively antagonize an endogenous NHP receptor, accessorymolecule, or substrate. Nucleotide constructs encoding such NHP productscan be used to genetically engineer host cells to express such productsin vivo; these genetically engineered cells function as “bioreactors” inthe body delivering a continuous supply of a NHP, a NHP peptide, or aNHP fusion protein to the body. Nucleotide constructs encodingfunctional NHP, mutant NHPs, as well as antisense and ribozye moleculescan also be used in “gene therapy” approaches for the modulation of NHPexpression. Thus, the invention also encompasses pharmaceuticalformulations and methods for treating biological disorders.

[0042] Various aspects of the invention are described in greater detailin the subsections below.

5.1 The NHP Sequences

[0043] The cDNA sequences and the corresponding deduced amino acidsequences of the described NHP are presented in the Sequence Listing.SEQ ID NO:27 describes a NHP ORF as well as flanking regions. The NHPnucleotides were obtained from human cDNA libraries using probes and/orprimers generated from human gene-trapped sequence tags. Expressionanalysis has provided evidence that the described NHPs are widelyexpressed in both human tissues as well as gene trapped human cells.

5.2 NHPs and NHP Polypeptides

[0044] NHPs, NHP polypeptides, NHP peptide fragments, mutated,truncated, or deleted forms of NHP, and/or NHP fusion proteins can beprepared for a variety of uses. These uses include, but are not limitedto, the generation of antibodies, as reagents in diagnostic assays, theidentification of other cellular gene products related to a NHP, asreagents in assays for screening for compounds that can be aspharmaceutical reagents useful in the therapeutic treatment of mental,biological, or medical disorders and disease.

[0045] The Sequence Listing discloses the amino acid sequence encoded bythe described NHP polynucleotides. The NHPs display initiatormethionines in DNA sequence contexts consistent with a translationinitiation site, and display a consensus signal sequence characteristicof secreted proteins.

[0046] The NHP amino acid sequences of the invention include the aminoacid sequences presented in the Sequence Listing as well as analoguesand derivatives thereof, as well as any oliqopeptide sequence of atleast about 10-40, generally about 12-35, or about 16-30 amino acids inlength first disclosed in the Sequence Listing. Further, correspondingNHP homologues from other species are encompassed by the invention. Infact, any NHP encoded by the NHP nucleotide sequences described aboveare within the scope of the invention, as are any novel polynucleotidesequences encoding all or any novel portion of an amino acid sequencepresented in the Sequence Listing. The degenerate nature of the geneticcode is well known, and, accordingly, each amino acid presented in theSequence Listing, is generically representative of the well knownnucleic acid “triplet” codon, or in many cases codons, that can encodethe amino acid. As such, as contemplated herein, the amino acidsequences presented in the Sequence Listing, when taken together withthe genetic code (see, for example, Table 4-1 at page 109 of “MolecularCell Biology”, 1986, J. Darnell et al. eds., Scientific American Books,New York, N.Y., herein incorporated by reference) are genericallyrepresentative of all the various permutations and combinations ofnucleic acid sequences that can encode such amino acid sequences.

[0047] The invention also encompasses proteins that are functionallyequivalent to the NHPs encoded by the presently described nucleotidesequences as judged by any of a number of criteria, including, but notlimited to, the ability to bind and cleave a substrate of a NHP, or theability to effect an identical or complementary downstream pathway, or achange in cellular metabolism (e.g., proteolytic activity, ion flux,tyrosine phosphorylation, etc.). Such functionally equivalent NHPproteins include, but are not limited to, additions or substitutions ofamino acid residues within the amino acid sequence encoded by the NHPnucleotide sequences described above, but which result in a silentchange, thus producing a functionally equivalent gene product. Aminoacid substitutions can be made on the basis of similarity in polarity,charge, solubility, hydrophobicity, hydrophilicity, and/or theamphipathic nature of the residues involved. For example, nonpolar(hydrophobic) amino acids include alanine, leucine, isoleucine, valine,proline, phenylalanine, tryptophan, and methionine; polar neutral aminoacids include glycine, serine, threonine, cysteine, tyrosine,asparagine, and glutamine; positively charged (basic) amino acidsinclude arginine, lysine, and histidine; and negatively charged (acidic)amino acids include aspartic acid and glutamic acid.

[0048] A variety of host-expression vector systems can be used toexpress the NHP nucleotide sequences of the invention. Where, as in thepresent instance, the NHP products or NHP polypeptides are thought to besoluble or secreted molecules, the peptide or polypeptide can berecovered from the culture media. Such expression systems also encompassengineered host cells that express a NHP, or a functional equivalent, insitu. Purification or enrichment of NHP from such expression systems canbe accomplished using appropriate detergents and lipid micelles andmethods well known to those skilled in the art. However, such engineeredhost cells themselve's may be used in situations where it is importantnot only to retain the structural and functional characteristics of theNHP, but to assess biological activity, e.g., in drug screening assays.

[0049] The expression systems that may be used for purposes of theinvention include but are not limited to microorganisms such as bacteria(e.g., E. coli, B. subtilis) transformed with recombinant bacteriophageDNA, plasmid DNA or cosmid DNA expression vectors containing NHPnucleotide sequences; yeast (e.g., Saccharomyces, Pichia) transformedwith recombinant yeast expression vectors containing NHP encodingnucleotide sequences; insect cell systems infected with recombinantvirus expression vectors (e.g., baculovirus) containing NHP sequences;plant cell systems infected with recombinant virus expression vectors(e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) ortransformed with recombinant plasmid expression vectors (e.g., Tiplasmid) containing NHP nucleotide sequences; or mammalian cell systems(e.g., COS, CHO, BHK, 293, 3T3) harboring recombinant expressionconstructs containing promoters derived from the genome of mammaliancells (e.g., metallothionein promoter) or from mammalian viruses (e.g.,the adenovirus late promoter; the vaccinia virus 7.5K promoter).

[0050] In bacterial systems, a number of expression vectors may beadvantageously selected depending upon the use intended for the NHPproduct being expressed. For example, when a large quantity of such aprotein is to be produced for the generation of pharmaceuticalcompositions of or containing NHP, or for raising antibodies to a NHP,vectors that direct the expression of high levels of fusion proteinproducts that are readily purified may be desirable. Such vectorsinclude, but are not limited, to the E. coli expression vector pUR278(Ruther et al., 1983, EMBO J. 2:1791), in which a NHP coding sequencemay be ligated individually into the vector in frame with the lacZcoding region so that a fusion protein is produced;.pIN vectors (Inouye& Inouye, 1985, Nucleic Acids Res. 13:3101-3109; Van Heeke & Schuster,1989, J. Biol. Chem. 264:5503-5509); and the like. pGEX vectors(Pharmacia or American Type Culture Collection) can also be used toexpress foreign polypeptides as fusion proteins with glutathioneS-transferase (GST). In general, such fusion proteins are soluble andcan easily be purified from lysed cells by adsorption toglutathione-agarose beads followed by elution in the presence of freeglutathione. The PGEX vectors are designed to include thrombin or factorXa protease cleavage sites so that the cloned target gene product can bereleased from the GST moiety.

[0051] In an insect system, Autographa californica nuclear polyhidrosisvirus. (AcNPV) is used as a vector to express foreign sequences. Thevirus grows in Spodoptera frugiperda cells. A NHP coding sequence can becloned individually into non-essential regions (for example thepolyhedrin gene) of the virus and placed under control of an AcNPVpromoter (for example the polyhedrin promoter). Successful insertion ofNHP coding sequence will result in inactivation of the polyhedrin geneand production of non-occluded recombinant virus (i.e., virus lackingthe proteinacebus coat coded for by the polyhedrin gene). Theserecombinant viruses are then used to infect Spodoptera frugiperda cellsin which the inserted sequence is expressed (e.g., see Smith et al.,1983, J. Virol. 46: 584; Smith, U.S. Pat. No. 4,215,051).

[0052] In mammalian host cells, a number of viral-based expressionsystems may be utilized. In cases where an adenovirus is used as anexpression vector, the NHP nucleotide sequence of interest may beligated to an adenovirus transcription/translation control complex,e.g., the late promoter and tripartite leader sequence. This chimericgene may then be inserted in the adenovirus genome by in vitro or invivo recombination. Insertion in a non-essential region of the viralgenome (e.g., region E1 or E3) will result in a recombinant virus thatis viable and capable of expressing a NHP product in infected hosts(e.g., See Logan & Shenk, 1984, Proc. Natl. Acad. Sci. USA81:3655-3659). Specific. initiation signals may also be required forefficient translation of inserted NHP nucleotide sequences. Thesesignals include the ATG initiation codon and adjacent sequences. Incases where an entire NHP gene or cDNA, including its own initiationcodon and adjacent sequences, is inserted into the appropriateexpression vector, no additional translational control signals may beneeded. However, in cases where only a portion of a NHP coding sequenceis inserted, exogenous translational control signals, including,perhaps, the ATG initiation codon, must be provided. Furthermore, theinitiation codon must be in phase with the reading frame of the desiredcoding sequence to ensure translation of the entire insert. Theseexogenous translational control signals and initiation codons can be ofa variety of origins, both natural and synthetic. The efficiency ofexpression can be enhanced by the inclusion of appropriate transcriptionenhancer elements, transcription terminators, etc. (See Bitter et al.,1987, Methods in Enzymol. 153:516-544).

[0053] In addition, a host cell strain may be chosen that modulates theexpression of the inserted sequences, or modifies and processes the geneproduct in the specific fashion desired. Such modifications (e.g.,glycosylation) and processing (e.g., cleavages of protein products maybe important for the function of the protein. Different host cells havecharacteristic and specific mechanisms for the post-translationalprocessing and modification of proteins and gene products. Appropriatecell lines or host systems can be chosen to ensure the correctmodification and processing of the foreign protein expressed. To thisend, eukaryotic host cells that possess the cellular machinery forproper processing of the primary transcript, glycosylation, andphosphorylation of the gene product may be used. Such mammalian hostcells include, but are not limited to, CHO, VERO, BHK, HeLa, COS, MDCK,293, 3T3, WI38, and in particular, human cell lines.

[0054] For long-term, high-yield production of recombinant proteins,stable expression is preferred. For example, cell lines which stablyexpress the NHP sequences described above can be engineered. Rather thanusing expression vectors which contain viral origins of replication,host cells can be transformed with DNA controlled by appropriateexpression control elements (e.g., promoter, enhancer sequences,transcription terminators, polyadenylation sites, etc.), and aDelectable marker. Following the introduction of the foreign DNA,engineered cells may be allowed to grow for 1-2 days in an enrichedmedia, and then are switched to a selective media. The selectable markerin the recombinant plasmid confers resistance to the selection andallows cells to stably integrate the plasmid into their chromosomes andgrow to form foci which in turn can be cloned and expanded into celllines. This method may advantageously be used to engineer cell lineswhich express the NHP product. Such engineered cell lines may beparticularly useful in screening and evaluation of compounds that affectthe endogenous activity of the NHP product.

[0055] A number of selection systems may be used, including but notlimited to the herpes simplex virus thymidine kinase (Wigler, et al.,1977, Cell 11:223), hypoxanthine-guanine phosphoribosyltransferase(Szybalska & Szybalski, 1962, Proc. Natl. Acad. Sci. USA 48:2026), andadenine phosphoribosyltransferase (Lowy, et al., 1980, Cell 22:817)genes can be employed in tk⁻, hgprt⁻ or aprt⁻ cells, respectively. Also,antimetabolite resistance can be used as the basis of selection for thefollowing genes: dhfr, which confers resistance to methotrexate (Wigler,et al., 1980, Natl. Acad. Sci. USA 77:3567; O'Hare, et al., 1981, Proc.Natl. Acad. Sci. USA 78:1527); gpt, which confers resistance tomycophenolic acid:(Mulligan & Berg, 1981, Proc. Natl. Acad. Sci. USA78:2072); neo, which confers resistance to the aminoglycoside G-418(Colberre-Garapin, et al., 1981, J. Mol. Biol. 150:1); and hygro, whichconfers resistance to hygromycin (Santerre, et al., 1984, Gene 30:147).

[0056] Alternatively, any fusion protein can be readily purified byutilizing an antibody specific for the fusion protein being expressed.For example, a system described by Janknecht et al. allows for the readypurification of non-denatured fusion proteins expressed in human celllines (Janknecht, et al., 1991, Proc. Natl. Acad. Sci. USA88:8972-8976). In this system, the gene of interest is subcloned into avaccinia recombination plasmid such that the gene's open reading frameis translationally fused to an amino-terminal tag consisting of sixhistidine residues. Extracts from cells infected with recombinantvaccinia virus are loaded onto Ni²⁺-nitriloacetic acid-agarose columnsand histidine-tagged proteins are selectively eluted withimidazole-containing buffers.

[0057] Also encompassed by the present invention are fusion proteinsthat direct the NHP to a target organ and/or facilitate transport acrossthe membrane into the cytosol. Conjugation of NHPs to antibody moleculesor their Fab fragments could be used to target cells bearing aparticular epitope. Attaching the appropriate signal sequence to the NHPwould also transport the NHP to the desired location within the cell.Alternatively targeting of NHP or its nucleic acid sequence might beachieved using liposome or lipid complex based delivery systems. Suchtechnologies are described in Liposomes: A Practical Approach, New RRCed., Oxford University Press, New York and in U.S. Pat. Nos. 4,594,595,5,459,127, 5,948,767 and 6,110,490 and their respective disclosureswhich are herein incorporated by reference in their entirety.Additionally embodied are novel protein constructs engineered in such away that they facilitate transport of the NHP to the target site ordesired organ, where they cross the cell membrane and/or the nucleuswhere the NHP can exert its functional activity. This goal may beachieved by coupling of the NHP to a cytokine or other ligand thatprovides targeting specificity, and/or to a protein transducing domain(see generally U.S. applications Ser. No. 60/111,701 and 60/056,713,both of which are herein incorporated by reference, for example's ofsuch transducing sequences) to facilitate passage across cellularmembranes and can optionally be engineered to include nuclearlocalization sequences.

5.3 Antibodies to NHP Products

[0058] Antibodies that specifically recognize one or more epitopes of aNHP, or epitopes of conserved variants of a NHP, or peptide fragments ofa NHP are also encompassed by the invention. Such antibodies include butare not limited to polyclonal antibodies, monoclonal antibodies (mAbs),humanized or chimeric antibodies, single chain antibodies, Fabfragments, F(ab′)₂ fragments, fragments produced by a Fab expressionlibrary, anti-idiotypic (anti-Id) antibodies, and epitope-bindingfragments of any of the above.

[0059] The antibodies of the invention may be used, for example, in thedetection of NHP in a biological sample and may, therefore, be utilizedas part of a diagnostic or prognostic technique whereby patients may betested for abnormal amounts of NHP. Such antibodies may also be utilizedin conjunction with, for example, compound screening schemes for theevaluation of the effect of test compounds on expression and/or activityof a NHP gene product. Additionally, such antibodies can be used inconjunction gene therapy to, for example, evaluate the normal and/orengineered NHP-expressing cells prior to their introduction into thepatient. Such antibodies may additionally be used as a method for theinhibition of abnormal NHP activity. Thus, such antibodies may,therefore, be utilized as part of treatment methods.

[0060] For the production of antibodies, various host animals may beimmunized by injection with the NHP, an NHP peptide (e.g., onecorresponding to a functional domain of an NHP), truncated NHPpolypeptides (NHP in which one or more domains have been deleted),functional equivalents of the NHP or mutated variant of the NHP. Suchhost animals may include but are not limited to pigs, rabbits, mice,goats, and rats, to name but a few. Various adjuvants may be used toincrease the immunological response, depending on the host species,including but not limited to Freund's adjuvant (complete andincomplete), mineral salts such as aluminum hydroxide or aluminumphosphate, surface active substances such as lysolecithin, pluronicpolyols, polyanions, peptides, oil emulsions, and potentially usefulhuman adjuvants such as BCG (bacille Calmette-Guerin) andCorynebacterium parvum. Alternatively, the immune response could beenhanced by combination and or coupling with molecules such as keyholelimpet hemocyanin, tetanus toxoid, diptheria toxoid, ovalbumin, choleratoxin or fragments thereof. Polyclonal antibodies are heterogeneouspopulations of antibody molecules derived from the sera of the immunizedanimals.

[0061] Monoclonal antibodies, which are homogeneous populations ofantibodies to a particular antigen, can be obtained by any techniquewhich provides for the production of antibody molecules by continuouscell lines in culture. These include, but are not limited to, thehybridoma technique of Kohler and Milstein, (1975, Nature 256:495-497;and U.S. Pat. No. 4,376,110), the human B-cell hybridoma technique(Kosbor et al., 1983, Immunology Today 4:72; Cole et al., 1983, Proc.Natl. Acad. Sci. USA 80:2026-2030), and the EBV-hybridoma technique(Cole et al., 1985, Monoclonal Antibodies And Cancer Therapy, Alan R.Liss, Inc., pp. 77-96). Such antibodies may be of any immunoglobulinclass including IgG, IgM, IgE, IgA, IgD and any subclass thereof. Thehybridoma producing the mAb of this invention may be cultivated in vitroor in vivo. Production of high titers of mabs in vivo makes this thepresently preferred method of production.

[0062] In addition, techniques developed for the production of “chimericantibodies” (Morrison et al., 1984, Proc. Natl. Acad. Sci.,81:6851-6855; Neuberger et al., 1984, Nature, 312:604-608; Takeda etal., 1985, Nature, 314:452-454) by splicing the genes from a mouseantibody molecule of appropriate antigen specificity together with genesfrom a human antibody molecule of appropriate biological activity can beused. A chimeric antibody is a molecule in which different portions arederived from different animal species, such as those having a variableregion derived from a murine mAb and a human immunoglobulin constantregion. Such technologies are described in U.S. Pat. Nos. 6,075,181 and5,877,397 and their respective disclosures which are herein incorporatedby reference in their entirety. Also encompassed by the presentinvention is the use of fully humanized monoclonal antibodies asdescribed in U.S. Pat. No. 6,150,584 and respective disclosures whichare herein incorporated by reference in their entirety.

[0063] Alternatively, techniques described for the production of singlechain antibodies (U.S. Pat. No. 4,946,778; Bird, 1988, Science242:423-426; Huston et al., 1988, Proc. Natl. Acad. Sci. USA85:5879-5883; and Ward et al., 1989, Nature 341:544-546) can be adaptedto produce single chain antibodies against NHP gene products. Singlechain antibodies are formed by linking the heavy and light chainfragments of the Fv region via an amino acid bridge, resulting in asingle chain polypeptide.

[0064] Antibody fragments which recognize specific epitopes may begenerated by known techniques. For example, such fragments include, butare not limited to: the F(ab′)₂ fragments which can be produced bypepsin digestion of the antibody molecule and the Fab fragments whichcan be generated by reducing the disulfide bridges of the F(ab′)₂fragments. Alternatively, Fab expression libraries may be constructed(Huse et al., 1989, Science, 246:1275-1281) to allow rapid and easyidentification of monoclonal Fab fragments with the desired specificity.

[0065] Antibodies to a NHP can, in turn, be utilized to generateanti-idiotype antibodies that “mimic” a given NHP, using techniques wellknown to those skilled in the art. (See, e.g., Greenspan & Bona, 1993,FASEB J 7(5):437-444; and Nissinoff, 1991, J. Immunol.147(8):2429-2438). For example antibodies which bind to a NHP domain andcompetitively inhibit the binding of NHP to its cognate receptor can beused to generate anti-idiotypes that “mimic” the NHP and, therefore,bind and activate or neutralize a receptor. Such anti-idiotypicantibodies or Fab fragments of such anti-idiotypes can be used intherapeutic regimens involving a NHP signaling pathway.

[0066] The present invention is not to be limited in scope by thespecific embodiments described herein, which are intended as singleillustrations of individual aspects of the invention, and functionallyequivalent methods and components are within the scope of the invention.Indeed, various modifications of the invention, in addition to thoseshown and described herein will become apparent to those skilled in theart from the foregoing description. Such modifications are intended tofall within the scope of the appended claims. All cited publications,patents, and patent applications are herein incorporated by reference intheir entirety.

1 27 1 1524 DNA homo sapiens 1 atgccttggc tgctctcagc ccccaagctggttcccgctg tagcaaacgt ccgcggcctc 60 tcaggatgta tgttgtgttc acagcgaaggtactcccttc agcctgtccc agaaaggagg 120 attccaaacc gatacttagg ccagcccagcccctttacac acccacacct cctcagacca 180 ggggaggtaa ctccaggact atctcaggtggaatatgcac ttcgcagaca caaactaatg 240 tctctgatcc agaaggaagc tcaagggcagagtgggacag accagacagt ggttgtgctc 300 tccaacccta catactacat gagcaacgatattccctata ctttccacca agacaacaat 360 ttcctgtacc tatgtggatt ccaagagcctgatagcattc ttgtccttca gagcctccct 420 ggcaaacaat taccatcaca caaagccatactttttgtgc ctcggcgaga tcccagtcga 480 gaactttggg atggtccgcg atctggcactgatggagcaa tagctctaac tggagtagac 540 gaagcctata cgctagaaga atttcaacatcttctaccaa aaatgaaagc tgagacgaac 600 atggtttggt atgactggat gaggccctcacatgcacagc ttcactctga ctatatgcag 660 cccctgactg aggccaaagc caagagcaagaacaaggttc ggggtgttca gcagctgata 720 cagcgcctcc ggctgatcaa gtctcctgcagaaattgaac gaatgcagat tgctgggaag 780 ctgacatcac aggctttcat agaaaccatgttcaccagta aagcccctgt ggaagaagcc 840 tttctttatg ctaagtttga atttgaatgccgggctcgtg gcgcagacat tttagcctat 900 ccacctgtgg tggctggtgg taatcggtcaaacactttgc actatgtgaa aaataatcaa 960 ctcatcaagg atggggaaat ggtgcttctggatggaggtt gtgagtcttc ctgctatgtg 1020 agtgacatca cacgtacgtg gccagtcaatggcaggttca ccgcacctca ggcagaactc 1080 tatgaagccg ttctagagat ccaaagagattgtttggccc tctgcttccc tgggacaagc 1140 ttggagaaca tctacagcat gatgctgaccctgataggac agaagcttaa agacttgggg 1200 atcatgaaga acattaagga aaataatgccttcaaggctg ctcgaaaata ctgtcctcat 1260 catgttggcc actacctcgg gatggatgtccatgacactc cagacatgcc ccgttccctc 1320 cctctgcagc ctgggatggt aatcacaattgagcccggca tttatattcc agaggatgac 1380 aaagatgccc cagagaagtt tcggggtcttggtgtacgaa ttgaggatga tgtagtggtg 1440 actcaggact cacctctcat cctttctgcagactgtccca aagagatgaa tgacattgaa 1500 cagatatgca gccaggcttc ttga 1524 2507 PRT homo sapiens 2 Met Pro Trp Leu Leu Ser Ala Pro Lys Leu Val ProAla Val Ala Asn 1 5 10 15 Val Arg Gly Leu Ser Gly Cys Met Leu Cys SerGln Arg Arg Tyr Ser 20 25 30 Leu Gln Pro Val Pro Glu Arg Arg Ile Pro AsnArg Tyr Leu Gly Gln 35 40 45 Pro Ser Pro Phe Thr His Pro His Leu Leu ArgPro Gly Glu Val Thr 50 55 60 Pro Gly Leu Ser Gln Val Glu Tyr Ala Leu ArgArg His Lys Leu Met 65 70 75 80 Ser Leu Ile Gln Lys Glu Ala Gln Gly GlnSer Gly Thr Asp Gln Thr 85 90 95 Val Val Val Leu Ser Asn Pro Thr Tyr TyrMet Ser Asn Asp Ile Pro 100 105 110 Tyr Thr Phe His Gln Asp Asn Asn PheLeu Tyr Leu Cys Gly Phe Gln 115 120 125 Glu Pro Asp Ser Ile Leu Val LeuGln Ser Leu Pro Gly Lys Gln Leu 130 135 140 Pro Ser His Lys Ala Ile LeuPhe Val Pro Arg Arg Asp Pro Ser Arg 145 150 155 160 Glu Leu Trp Asp GlyPro Arg Ser Gly Thr Asp Gly Ala Ile Ala Leu 165 170 175 Thr Gly Val AspGlu Ala Tyr Thr Leu Glu Glu Phe Gln His Leu Leu 180 185 190 Pro Lys MetLys Ala Glu Thr Asn Met Val Trp Tyr Asp Trp Met Arg 195 200 205 Pro SerHis Ala Gln Leu His Ser Asp Tyr Met Gln Pro Leu Thr Glu 210 215 220 AlaLys Ala Lys Ser Lys Asn Lys Val Arg Gly Val Gln Gln Leu Ile 225 230 235240 Gln Arg Leu Arg Leu Ile Lys Ser Pro Ala Glu Ile Glu Arg Met Gln 245250 255 Ile Ala Gly Lys Leu Thr Ser Gln Ala Phe Ile Glu Thr Met Phe Thr260 265 270 Ser Lys Ala Pro Val Glu Glu Ala Phe Leu Tyr Ala Lys Phe GluPhe 275 280 285 Glu Cys Arg Ala Arg Gly Ala Asp Ile Leu Ala Tyr Pro ProVal Val 290 295 300 Ala Gly Gly Asn Arg Ser Asn Thr Leu His Tyr Val LysAsn Asn Gln 305 310 315 320 Leu Ile Lys Asp Gly Glu Met Val Leu Leu AspGly Gly Cys Glu Ser 325 330 335 Ser Cys Tyr Val Ser Asp Ile Thr Arg ThrTrp Pro Val Asn Gly Arg 340 345 350 Phe Thr Ala Pro Gln Ala Glu Leu TyrGlu Ala Val Leu Glu Ile Gln 355 360 365 Arg Asp Cys Leu Ala Leu Cys PhePro Gly Thr Ser Leu Glu Asn Ile 370 375 380 Tyr Ser Met Met Leu Thr LeuIle Gly Gln Lys Leu Lys Asp Leu Gly 385 390 395 400 Ile Met Lys Asn IleLys Glu Asn Asn Ala Phe Lys Ala Ala Arg Lys 405 410 415 Tyr Cys Pro HisHis Val Gly His Tyr Leu Gly Met Asp Val His Asp 420 425 430 Thr Pro AspMet Pro Arg Ser Leu Pro Leu Gln Pro Gly Met Val Ile 435 440 445 Thr IleGlu Pro Gly Ile Tyr Ile Pro Glu Asp Asp Lys Asp Ala Pro 450 455 460 GluLys Phe Arg Gly Leu Gly Val Arg Ile Glu Asp Asp Val Val Val 465 470 475480 Thr Gln Asp Ser Pro Leu Ile Leu Ser Ala Asp Cys Pro Lys Glu Met 485490 495 Asn Asp Ile Glu Gln Ile Cys Ser Gln Ala Ser 500 505 3 210 DNAhomo sapiens 3 atgccttggc tgctctcagc ccccaagctg gttcccgctg tagcaaacgtccgcggcctc 60 tcaggatgta tgttgtgttc acagcgaagg tactcccttc agcctgtcccagaaaggagg 120 attccaaacc gatacttagg ccagcccagc ccctttacac acccacacctcctcagacca 180 gactcgaatt cctgctggga agtcggctga 210 4 69 PRT homosapiens 4 Met Pro Trp Leu Leu Ser Ala Pro Lys Leu Val Pro Ala Val AlaAsn 1 5 10 15 Val Arg Gly Leu Ser Gly Cys Met Leu Cys Ser Gln Arg ArgTyr Ser 20 25 30 Leu Gln Pro Val Pro Glu Arg Arg Ile Pro Asn Arg Tyr LeuGly Gln 35 40 45 Pro Ser Pro Phe Thr His Pro His Leu Leu Arg Pro Asp SerAsn Ser 50 55 60 Cys Trp Glu Val Gly 65 5 873 DNA homo sapiens 5atgccttggc tgctctcagc ccccaagctg gttcccgctg tagcaaacgt ccgcggcctc 60tcaggatgta tgttgtgttc acagcgaagg tactcccttc agcctgtccc agaaaggagg 120attccaaacc gatacttagg ccagcccagc ccctttacac acccacacct cctcagacca 180ggggaggtaa ctccaggact atctcaggtg gaatatgcac ttcgcagaca caaactaatg 240tctctgatcc agaaggaagc tcaagggcag agtgggacag accagacagt ggttgtgctc 300tccaacccta catactacat gagcaacgat attccctata ctttccacca agacaacaat 360ttcctgtacc tatgtggatt ccaagagcct gatagcattc ttgtccttca gagcctccct 420ggcaaacaat taccatcaca caaagccata ctttttgtgc ctcggcgaga tcccagtcga 480gaactttggg atggtccgcg atctggcact gatggagcaa tagctctaac tggagtagac 540gaagcctata cgctagaaga atttcaacat cttctaccaa aaatgaaagt gctcttgcca 600gctcttcaaa aggaggtact gttctccaag aacgatccat gcatcacagc atcagaatca 660cctgctgaga cgaacatggt ttggtatgac tggatgaggc cctcacatgc acagcttcac 720tctgactata tgcagcccct gactgaggcc aaagccaaga gcaagaacaa ggttcggggt 780gttcagcagc tgatacagcg cctccggctg atcaagtctc ctgcagaaat tgaacgaatg 840cagattgctg ggaagctgac atcacaggta tga 873 6 290 PRT homo sapiens 6 MetPro Trp Leu Leu Ser Ala Pro Lys Leu Val Pro Ala Val Ala Asn 1 5 10 15Val Arg Gly Leu Ser Gly Cys Met Leu Cys Ser Gln Arg Arg Tyr Ser 20 25 30Leu Gln Pro Val Pro Glu Arg Arg Ile Pro Asn Arg Tyr Leu Gly Gln 35 40 45Pro Ser Pro Phe Thr His Pro His Leu Leu Arg Pro Gly Glu Val Thr 50 55 60Pro Gly Leu Ser Gln Val Glu Tyr Ala Leu Arg Arg His Lys Leu Met 65 70 7580 Ser Leu Ile Gln Lys Glu Ala Gln Gly Gln Ser Gly Thr Asp Gln Thr 85 9095 Val Val Val Leu Ser Asn Pro Thr Tyr Tyr Met Ser Asn Asp Ile Pro 100105 110 Tyr Thr Phe His Gln Asp Asn Asn Phe Leu Tyr Leu Cys Gly Phe Gln115 120 125 Glu Pro Asp Ser Ile Leu Val Leu Gln Ser Leu Pro Gly Lys GlnLeu 130 135 140 Pro Ser His Lys Ala Ile Leu Phe Val Pro Arg Arg Asp ProSer Arg 145 150 155 160 Glu Leu Trp Asp Gly Pro Arg Ser Gly Thr Asp GlyAla Ile Ala Leu 165 170 175 Thr Gly Val Asp Glu Ala Tyr Thr Leu Glu GluPhe Gln His Leu Leu 180 185 190 Pro Lys Met Lys Val Leu Leu Pro Ala LeuGln Lys Glu Val Leu Phe 195 200 205 Ser Lys Asn Asp Pro Cys Ile Thr AlaSer Glu Ser Pro Ala Glu Thr 210 215 220 Asn Met Val Trp Tyr Asp Trp MetArg Pro Ser His Ala Gln Leu His 225 230 235 240 Ser Asp Tyr Met Gln ProLeu Thr Glu Ala Lys Ala Lys Ser Lys Asn 245 250 255 Lys Val Arg Gly ValGln Gln Leu Ile Gln Arg Leu Arg Leu Ile Lys 260 265 270 Ser Pro Ala GluIle Glu Arg Met Gln Ile Ala Gly Lys Leu Thr Ser 275 280 285 Gln Val 2907 798 DNA homo sapiens 7 atgccttggc tgctctcagc ccccaagctg gttcccgctgtagcaaacgt ccgcggcctc 60 tcaggatgta tgttgtgttc acagcgaagg tactcccttcagcctgtccc agaaaggagg 120 attccaaacc gatacttagg ccagcccagc ccctttacacacccacacct cctcagacca 180 ggggaggtaa ctccaggact atctcaggtg gaatatgcacttcgcagaca caaactaatg 240 tctctgatcc agaaggaagc tcaagggcag agtgggacagaccagacagt ggttgtgctc 300 tccaacccta catactacat gagcaacgat attccctatactttccacca agacaacaat 360 ttcctgtacc tatgtggatt ccaagagcct gatagcattcttgtccttca gagcctccct 420 ggcaaacaat taccatcaca caaagccata ctttttgtgcctcggcgaga tcccagtcga 480 gaactttggg atggtccgcg atctggcact gatggagcaatagctctaac tggagtagac 540 gaagcctata cgctagaaga atttcaacat cttctaccaaaaatgaaagc tgagacgaac 600 atggtttggt atgactggat gaggccctca catgcacagcttcactctga ctatatgcag 660 cccctgactg aggccaaagc caagagcaag aacaaggttcggggtgttca gcagctgata 720 cagcgcctcc ggctgatcaa gtctcctgca gaaattgaacgaatgcagat tgctgggaag 780 ctgacatcac aggtatga 798 8 265 PRT homo sapiens8 Met Pro Trp Leu Leu Ser Ala Pro Lys Leu Val Pro Ala Val Ala Asn 1 5 1015 Val Arg Gly Leu Ser Gly Cys Met Leu Cys Ser Gln Arg Arg Tyr Ser 20 2530 Leu Gln Pro Val Pro Glu Arg Arg Ile Pro Asn Arg Tyr Leu Gly Gln 35 4045 Pro Ser Pro Phe Thr His Pro His Leu Leu Arg Pro Gly Glu Val Thr 50 5560 Pro Gly Leu Ser Gln Val Glu Tyr Ala Leu Arg Arg His Lys Leu Met 65 7075 80 Ser Leu Ile Gln Lys Glu Ala Gln Gly Gln Ser Gly Thr Asp Gln Thr 8590 95 Val Val Val Leu Ser Asn Pro Thr Tyr Tyr Met Ser Asn Asp Ile Pro100 105 110 Tyr Thr Phe His Gln Asp Asn Asn Phe Leu Tyr Leu Cys Gly PheGln 115 120 125 Glu Pro Asp Ser Ile Leu Val Leu Gln Ser Leu Pro Gly LysGln Leu 130 135 140 Pro Ser His Lys Ala Ile Leu Phe Val Pro Arg Arg AspPro Ser Arg 145 150 155 160 Glu Leu Trp Asp Gly Pro Arg Ser Gly Thr AspGly Ala Ile Ala Leu 165 170 175 Thr Gly Val Asp Glu Ala Tyr Thr Leu GluGlu Phe Gln His Leu Leu 180 185 190 Pro Lys Met Lys Ala Glu Thr Asn MetVal Trp Tyr Asp Trp Met Arg 195 200 205 Pro Ser His Ala Gln Leu His SerAsp Tyr Met Gln Pro Leu Thr Glu 210 215 220 Ala Lys Ala Lys Ser Lys AsnLys Val Arg Gly Val Gln Gln Leu Ile 225 230 235 240 Gln Arg Leu Arg LeuIle Lys Ser Pro Ala Glu Ile Glu Arg Met Gln 245 250 255 Ile Ala Gly LysLeu Thr Ser Gln Val 260 265 9 636 DNA homo sapiens 9 atgtctctgatccagaagga agctcaaggg cagagtggga cagaccagac agtggttgtg 60 ctctccaaccctacatacta catgagcaac gatattccct atactttcca ccaagacaac 120 aatttcctgtacctatgtgg attccaagag cctgatagca ttcttgtcct tcagagcctc 180 cctggcaaacaattaccatc acacaaagcc atactttttg tgcctcggcg agatcccagt 240 cgagaactttgggatggtcc gcgatctggc actgatggag caatagctct aactggagta 300 gacgaagcctatacgctaga agaatttcaa catcttctac caaaaatgaa agtgctcttg 360 ccagctcttcaaaaggaggt actgttctcc aagaacgatc catgcatcac agcatcagaa 420 tcacctgctgagacgaacat ggtttggtat gactggatga ggccctcaca tgcacagctt 480 cactctgactatatgcagcc cctgactgag gccaaagcca agagcaagaa caaggttcgg 540 ggtgttcagcagctgataca gcgcctccgg ctgatcaagt ctcctgcaga aattgaacga 600 atgcagattgctgggaagct gacatcacag gtatga 636 10 211 PRT homo sapiens 10 Met Ser LeuIle Gln Lys Glu Ala Gln Gly Gln Ser Gly Thr Asp Gln 1 5 10 15 Thr ValVal Val Leu Ser Asn Pro Thr Tyr Tyr Met Ser Asn Asp Ile 20 25 30 Pro TyrThr Phe His Gln Asp Asn Asn Phe Leu Tyr Leu Cys Gly Phe 35 40 45 Gln GluPro Asp Ser Ile Leu Val Leu Gln Ser Leu Pro Gly Lys Gln 50 55 60 Leu ProSer His Lys Ala Ile Leu Phe Val Pro Arg Arg Asp Pro Ser 65 70 75 80 ArgGlu Leu Trp Asp Gly Pro Arg Ser Gly Thr Asp Gly Ala Ile Ala 85 90 95 LeuThr Gly Val Asp Glu Ala Tyr Thr Leu Glu Glu Phe Gln His Leu 100 105 110Leu Pro Lys Met Lys Val Leu Leu Pro Ala Leu Gln Lys Glu Val Leu 115 120125 Phe Ser Lys Asn Asp Pro Cys Ile Thr Ala Ser Glu Ser Pro Ala Glu 130135 140 Thr Asn Met Val Trp Tyr Asp Trp Met Arg Pro Ser His Ala Gln Leu145 150 155 160 His Ser Asp Tyr Met Gln Pro Leu Thr Glu Ala Lys Ala LysSer Lys 165 170 175 Asn Lys Val Arg Gly Val Gln Gln Leu Ile Gln Arg LeuArg Leu Ile 180 185 190 Lys Ser Pro Ala Glu Ile Glu Arg Met Gln Ile AlaGly Lys Leu Thr 195 200 205 Ser Gln Val 210 11 804 DNA homo sapiens 11atgttgtgtt cacagcgaag gtactccctt cagcctgtcc cagaaaggag gattccaaac 60cgatacttag gccagcccag cccctttaca cacccacacc tcctcagacc aggggaggta 120actccaggac tatctcaggt ggaatatgca cttcgcagac acaaactaat gtctctgatc 180cagaaggaag ctcaagggca gagtgggaca gaccagacag tggttgtgct ctccaaccct 240acatactaca tgagcaacga tattccctat actttccacc aagacaacaa tttcctgtac 300ctatgtggat tccaagagcc tgatagcatt cttgtccttc agagcctccc tggcaaacaa 360ttaccatcac acaaagccat actttttgtg cctcggcgag atcccagtcg agaactttgg 420gatggtccgc gatctggcac tgatggagca atagctctaa ctggagtaga cgaagcctat 480acgctagaag aatttcaaca tcttctacca aaaatgaaag tgctcttgcc agctcttcaa 540aaggaggtac tgttctccaa gaacgatcca tgcatcacag catcagaatc acctgctgag 600acgaacatgg tttggtatga ctggatgagg ccctcacatg cacagcttca ctctgactat 660atgcagcccc tgactgaggc caaagccaag agcaagaaca aggttcgggg tgttcagcag 720ctgatacagc gcctccggct gatcaagtct cctgcagaaa ttgaacgaat gcagattgct 780gggaagctga catcacaggt atga 804 12 267 PRT homo sapiens 12 Met Leu CysSer Gln Arg Arg Tyr Ser Leu Gln Pro Val Pro Glu Arg 1 5 10 15 Arg IlePro Asn Arg Tyr Leu Gly Gln Pro Ser Pro Phe Thr His Pro 20 25 30 His LeuLeu Arg Pro Gly Glu Val Thr Pro Gly Leu Ser Gln Val Glu 35 40 45 Tyr AlaLeu Arg Arg His Lys Leu Met Ser Leu Ile Gln Lys Glu Ala 50 55 60 Gln GlyGln Ser Gly Thr Asp Gln Thr Val Val Val Leu Ser Asn Pro 65 70 75 80 ThrTyr Tyr Met Ser Asn Asp Ile Pro Tyr Thr Phe His Gln Asp Asn 85 90 95 AsnPhe Leu Tyr Leu Cys Gly Phe Gln Glu Pro Asp Ser Ile Leu Val 100 105 110Leu Gln Ser Leu Pro Gly Lys Gln Leu Pro Ser His Lys Ala Ile Leu 115 120125 Phe Val Pro Arg Arg Asp Pro Ser Arg Glu Leu Trp Asp Gly Pro Arg 130135 140 Ser Gly Thr Asp Gly Ala Ile Ala Leu Thr Gly Val Asp Glu Ala Tyr145 150 155 160 Thr Leu Glu Glu Phe Gln His Leu Leu Pro Lys Met Lys ValLeu Leu 165 170 175 Pro Ala Leu Gln Lys Glu Val Leu Phe Ser Lys Asn AspPro Cys Ile 180 185 190 Thr Ala Ser Glu Ser Pro Ala Glu Thr Asn Met ValTrp Tyr Asp Trp 195 200 205 Met Arg Pro Ser His Ala Gln Leu His Ser AspTyr Met Gln Pro Leu 210 215 220 Thr Glu Ala Lys Ala Lys Ser Lys Asn LysVal Arg Gly Val Gln Gln 225 230 235 240 Leu Ile Gln Arg Leu Arg Leu IleLys Ser Pro Ala Glu Ile Glu Arg 245 250 255 Met Gln Ile Ala Gly Lys LeuThr Ser Gln Val 260 265 13 561 DNA homo sapiens 13 atgtctctga tccagaaggaagctcaaggg cagagtggga cagaccagac agtggttgtg 60 ctctccaacc ctacatactacatgagcaac gatattccct atactttcca ccaagacaac 120 aatttcctgt acctatgtggattccaagag cctgatagca ttcttgtcct tcagagcctc 180 cctggcaaac aattaccatcacacaaagcc atactttttg tgcctcggcg agatcccagt 240 cgagaacttt gggatggtccgcgatctggc actgatggag caatagctct aactggagta 300 gacgaagcct atacgctagaagaatttcaa catcttctac caaaaatgaa agctgagacg 360 aacatggttt ggtatgactggatgaggccc tcacatgcac agcttcactc tgactatatg 420 cagcccctga ctgaggccaaagccaagagc aagaacaagg ttcggggtgt tcagcagctg 480 atacagcgcc tccggctgatcaagtctcct gcagaaattg aacgaatgca gattgctggg 540 aagctgacat cacaggtatg a561 14 186 PRT homo sapiens 14 Met Ser Leu Ile Gln Lys Glu Ala Gln GlyGln Ser Gly Thr Asp Gln 1 5 10 15 Thr Val Val Val Leu Ser Asn Pro ThrTyr Tyr Met Ser Asn Asp Ile 20 25 30 Pro Tyr Thr Phe His Gln Asp Asn AsnPhe Leu Tyr Leu Cys Gly Phe 35 40 45 Gln Glu Pro Asp Ser Ile Leu Val LeuGln Ser Leu Pro Gly Lys Gln 50 55 60 Leu Pro Ser His Lys Ala Ile Leu PheVal Pro Arg Arg Asp Pro Ser 65 70 75 80 Arg Glu Leu Trp Asp Gly Pro ArgSer Gly Thr Asp Gly Ala Ile Ala 85 90 95 Leu Thr Gly Val Asp Glu Ala TyrThr Leu Glu Glu Phe Gln His Leu 100 105 110 Leu Pro Lys Met Lys Ala GluThr Asn Met Val Trp Tyr Asp Trp Met 115 120 125 Arg Pro Ser His Ala GlnLeu His Ser Asp Tyr Met Gln Pro Leu Thr 130 135 140 Glu Ala Lys Ala LysSer Lys Asn Lys Val Arg Gly Val Gln Gln Leu 145 150 155 160 Ile Gln ArgLeu Arg Leu Ile Lys Ser Pro Ala Glu Ile Glu Arg Met 165 170 175 Gln IleAla Gly Lys Leu Thr Ser Gln Val 180 185 15 729 DNA homo sapiens 15atgttgtgtt cacagcgaag gtactccctt cagcctgtcc cagaaaggag gattccaaac 60cgatacttag gccagcccag cccctttaca cacccacacc tcctcagacc aggggaggta 120actccaggac tatctcaggt ggaatatgca cttcgcagac acaaactaat gtctctgatc 180cagaaggaag ctcaagggca gagtgggaca gaccagacag tggttgtgct ctccaaccct 240acatactaca tgagcaacga tattccctat actttccacc aagacaacaa tttcctgtac 300ctatgtggat tccaagagcc tgatagcatt cttgtccttc agagcctccc tggcaaacaa 360ttaccatcac acaaagccat actttttgtg cctcggcgag atcccagtcg agaactttgg 420gatggtccgc gatctggcac tgatggagca atagctctaa ctggagtaga cgaagcctat 480acgctagaag aatttcaaca tcttctacca aaaatgaaag ctgagacgaa catggtttgg 540tatgactgga tgaggccctc acatgcacag cttcactctg actatatgca gcccctgact 600gaggccaaag ccaagagcaa gaacaaggtt cggggtgttc agcagctgat acagcgcctc 660cggctgatca agtctcctgc agaaattgaa cgaatgcaga ttgctgggaa gctgacatca 720caggtatga 729 16 242 PRT homo sapiens 16 Met Leu Cys Ser Gln Arg Arg TyrSer Leu Gln Pro Val Pro Glu Arg 1 5 10 15 Arg Ile Pro Asn Arg Tyr LeuGly Gln Pro Ser Pro Phe Thr His Pro 20 25 30 His Leu Leu Arg Pro Gly GluVal Thr Pro Gly Leu Ser Gln Val Glu 35 40 45 Tyr Ala Leu Arg Arg His LysLeu Met Ser Leu Ile Gln Lys Glu Ala 50 55 60 Gln Gly Gln Ser Gly Thr AspGln Thr Val Val Val Leu Ser Asn Pro 65 70 75 80 Thr Tyr Tyr Met Ser AsnAsp Ile Pro Tyr Thr Phe His Gln Asp Asn 85 90 95 Asn Phe Leu Tyr Leu CysGly Phe Gln Glu Pro Asp Ser Ile Leu Val 100 105 110 Leu Gln Ser Leu ProGly Lys Gln Leu Pro Ser His Lys Ala Ile Leu 115 120 125 Phe Val Pro ArgArg Asp Pro Ser Arg Glu Leu Trp Asp Gly Pro Arg 130 135 140 Ser Gly ThrAsp Gly Ala Ile Ala Leu Thr Gly Val Asp Glu Ala Tyr 145 150 155 160 ThrLeu Glu Glu Phe Gln His Leu Leu Pro Lys Met Lys Ala Glu Thr 165 170 175Asn Met Val Trp Tyr Asp Trp Met Arg Pro Ser His Ala Gln Leu His 180 185190 Ser Asp Tyr Met Gln Pro Leu Thr Glu Ala Lys Ala Lys Ser Lys Asn 195200 205 Lys Val Arg Gly Val Gln Gln Leu Ile Gln Arg Leu Arg Leu Ile Lys210 215 220 Ser Pro Ala Glu Ile Glu Arg Met Gln Ile Ala Gly Lys Leu ThrSer 225 230 235 240 Gln Val 17 1362 DNA homo sapiens 17 atgtctctgatccagaagga agctcaaggg cagagtggga cagaccagac agtggttgtg 60 ctctccaaccctacatacta catgagcaac gatattccct atactttcca ccaagacaac 120 aatttcctgtacctatgtgg attccaagag cctgatagca ttcttgtcct tcagagcctc 180 cctggcaaacaattaccatc acacaaagcc atactttttg tgcctcggcg agatcccagt 240 cgagaactttgggatggtcc gcgatctggc actgatggag caatagctct aactggagta 300 gacgaagcctatacgctaga agaatttcaa catcttctac caaaaatgaa agtgctcttg 360 ccagctcttcaaaaggaggt actgttctcc aagaacgatc catgcatcac agcatcagaa 420 tcacctgctgagacgaacat ggtttggtat gactggatga ggccctcaca tgcacagctt 480 cactctgactatatgcagcc cctgactgag gccaaagcca agagcaagaa caaggttcgg 540 ggtgttcagcagctgataca gcgcctccgg ctgatcaagt ctcctgcaga aattgaacga 600 atgcagattgctgggaagct gacatcacag gctttcatag aaaccatgtt caccagtaaa 660 gcccctgtggaagaagcctt tctttatgct aagtttgaat ttgaatgccg ggctcgtggc 720 gcagacattttagcctatcc acctgtggtg gctggtggta atcggtcaaa cactttgcac 780 tatgtgaaaaataatcaact catcaaggat ggggaaatgg tgcttctgga tggaggttgt 840 gagtcttcctgctatgtgag tgacatcaca cgtacgtggc cagtcaatgg caggttcacc 900 gcacctcaggcagaactcta tgaagccgtt ctagagatcc aaagagattg tttggccctc 960 tgcttccctgggacaagctt ggagaacatc tacagcatga tgctgaccct gataggacag 1020 aagcttaaagacttggggat catgaagaac attaaggaaa ataatgcctt caaggctgct 1080 cgaaaatactgtcctcatca tgttggccac tacctcggga tggatgtcca tgacactcca 1140 gacatgccccgttccctccc tctgcagcct gggatggtaa tcacaattga gcccggcatt 1200 tatattccagaggatgacaa agatgcccca gagaagtttc ggggtcttgg tgtacgaatt 1260 gaggatgatgtagtggtgac tcaggactca cctctcatcc tttctgcaga ctgtcccaaa 1320 gagatgaatgacattgaaca gatatgcagc caggcttctt ga 1362 18 453 PRT homo sapiens 18 MetSer Leu Ile Gln Lys Glu Ala Gln Gly Gln Ser Gly Thr Asp Gln 1 5 10 15Thr Val Val Val Leu Ser Asn Pro Thr Tyr Tyr Met Ser Asn Asp Ile 20 25 30Pro Tyr Thr Phe His Gln Asp Asn Asn Phe Leu Tyr Leu Cys Gly Phe 35 40 45Gln Glu Pro Asp Ser Ile Leu Val Leu Gln Ser Leu Pro Gly Lys Gln 50 55 60Leu Pro Ser His Lys Ala Ile Leu Phe Val Pro Arg Arg Asp Pro Ser 65 70 7580 Arg Glu Leu Trp Asp Gly Pro Arg Ser Gly Thr Asp Gly Ala Ile Ala 85 9095 Leu Thr Gly Val Asp Glu Ala Tyr Thr Leu Glu Glu Phe Gln His Leu 100105 110 Leu Pro Lys Met Lys Val Leu Leu Pro Ala Leu Gln Lys Glu Val Leu115 120 125 Phe Ser Lys Asn Asp Pro Cys Ile Thr Ala Ser Glu Ser Pro AlaGlu 130 135 140 Thr Asn Met Val Trp Tyr Asp Trp Met Arg Pro Ser His AlaGln Leu 145 150 155 160 His Ser Asp Tyr Met Gln Pro Leu Thr Glu Ala LysAla Lys Ser Lys 165 170 175 Asn Lys Val Arg Gly Val Gln Gln Leu Ile GlnArg Leu Arg Leu Ile 180 185 190 Lys Ser Pro Ala Glu Ile Glu Arg Met GlnIle Ala Gly Lys Leu Thr 195 200 205 Ser Gln Ala Phe Ile Glu Thr Met PheThr Ser Lys Ala Pro Val Glu 210 215 220 Glu Ala Phe Leu Tyr Ala Lys PheGlu Phe Glu Cys Arg Ala Arg Gly 225 230 235 240 Ala Asp Ile Leu Ala TyrPro Pro Val Val Ala Gly Gly Asn Arg Ser 245 250 255 Asn Thr Leu His TyrVal Lys Asn Asn Gln Leu Ile Lys Asp Gly Glu 260 265 270 Met Val Leu LeuAsp Gly Gly Cys Glu Ser Ser Cys Tyr Val Ser Asp 275 280 285 Ile Thr ArgThr Trp Pro Val Asn Gly Arg Phe Thr Ala Pro Gln Ala 290 295 300 Glu LeuTyr Glu Ala Val Leu Glu Ile Gln Arg Asp Cys Leu Ala Leu 305 310 315 320Cys Phe Pro Gly Thr Ser Leu Glu Asn Ile Tyr Ser Met Met Leu Thr 325 330335 Leu Ile Gly Gln Lys Leu Lys Asp Leu Gly Ile Met Lys Asn Ile Lys 340345 350 Glu Asn Asn Ala Phe Lys Ala Ala Arg Lys Tyr Cys Pro His His Val355 360 365 Gly His Tyr Leu Gly Met Asp Val His Asp Thr Pro Asp Met ProArg 370 375 380 Ser Leu Pro Leu Gln Pro Gly Met Val Ile Thr Ile Glu ProGly Ile 385 390 395 400 Tyr Ile Pro Glu Asp Asp Lys Asp Ala Pro Glu LysPhe Arg Gly Leu 405 410 415 Gly Val Arg Ile Glu Asp Asp Val Val Val ThrGln Asp Ser Pro Leu 420 425 430 Ile Leu Ser Ala Asp Cys Pro Lys Glu MetAsn Asp Ile Glu Gln Ile 435 440 445 Cys Ser Gln Ala Ser 450 19 1599 DNAhomo sapiens 19 atgccttggc tgctctcagc ccccaagctg gttcccgctg tagcaaacgtccgcggcctc 60 tcaggatgta tgttgtgttc acagcgaagg tactcccttc agcctgtcccagaaaggagg 120 attccaaacc gatacttagg ccagcccagc ccctttacac acccacacctcctcagacca 180 ggggaggtaa ctccaggact atctcaggtg gaatatgcac ttcgcagacacaaactaatg 240 tctctgatcc agaaggaagc tcaagggcag agtgggacag accagacagtggttgtgctc 300 tccaacccta catactacat gagcaacgat attccctata ctttccaccaagacaacaat 360 ttcctgtacc tatgtggatt ccaagagcct gatagcattc ttgtccttcagagcctccct 420 ggcaaacaat taccatcaca caaagccata ctttttgtgc ctcggcgagatcccagtcga 480 gaactttggg atggtccgcg atctggcact gatggagcaa tagctctaactggagtagac 540 gaagcctata cgctagaaga atttcaacat cttctaccaa aaatgaaagtgctcttgcca 600 gctcttcaaa aggaggtact gttctccaag aacgatccat gcatcacagcatcagaatca 660 cctgctgaga cgaacatggt ttggtatgac tggatgaggc cctcacatgcacagcttcac 720 tctgactata tgcagcccct gactgaggcc aaagccaaga gcaagaacaaggttcggggt 780 gttcagcagc tgatacagcg cctccggctg atcaagtctc ctgcagaaattgaacgaatg 840 cagattgctg ggaagctgac atcacaggct ttcatagaaa ccatgttcaccagtaaagcc 900 cctgtggaag aagcctttct ttatgctaag tttgaatttg aatgccgggctcgtggcgca 960 gacattttag cctatccacc tgtggtggct ggtggtaatc ggtcaaacactttgcactat 1020 gtgaaaaata atcaactcat caaggatggg gaaatggtgc ttctggatggaggttgtgag 1080 tcttcctgct atgtgagtga catcacacgt acgtggccag tcaatggcaggttcaccgca 1140 cctcaggcag aactctatga agccgttcta gagatccaaa gagattgtttggccctctgc 1200 ttccctggga caagcttgga gaacatctac agcatgatgc tgaccctgataggacagaag 1260 cttaaagact tggggatcat gaagaacatt aaggaaaata atgccttcaaggctgctcga 1320 aaatactgtc ctcatcatgt tggccactac ctcgggatgg atgtccatgacactccagac 1380 atgccccgtt ccctccctct gcagcctggg atggtaatca caattgagcccggcatttat 1440 attccagagg atgacaaaga tgccccagag aagtttcggg gtcttggtgtacgaattgag 1500 gatgatgtag tggtgactca ggactcacct ctcatccttt ctgcagactgtcccaaagag 1560 atgaatgaca ttgaacagat atgcagccag gcttcttga 1599 20 532PRT homo sapiens 20 Met Pro Trp Leu Leu Ser Ala Pro Lys Leu Val Pro AlaVal Ala Asn 1 5 10 15 Val Arg Gly Leu Ser Gly Cys Met Leu Cys Ser GlnArg Arg Tyr Ser 20 25 30 Leu Gln Pro Val Pro Glu Arg Arg Ile Pro Asn ArgTyr Leu Gly Gln 35 40 45 Pro Ser Pro Phe Thr His Pro His Leu Leu Arg ProGly Glu Val Thr 50 55 60 Pro Gly Leu Ser Gln Val Glu Tyr Ala Leu Arg ArgHis Lys Leu Met 65 70 75 80 Ser Leu Ile Gln Lys Glu Ala Gln Gly Gln SerGly Thr Asp Gln Thr 85 90 95 Val Val Val Leu Ser Asn Pro Thr Tyr Tyr MetSer Asn Asp Ile Pro 100 105 110 Tyr Thr Phe His Gln Asp Asn Asn Phe LeuTyr Leu Cys Gly Phe Gln 115 120 125 Glu Pro Asp Ser Ile Leu Val Leu GlnSer Leu Pro Gly Lys Gln Leu 130 135 140 Pro Ser His Lys Ala Ile Leu PheVal Pro Arg Arg Asp Pro Ser Arg 145 150 155 160 Glu Leu Trp Asp Gly ProArg Ser Gly Thr Asp Gly Ala Ile Ala Leu 165 170 175 Thr Gly Val Asp GluAla Tyr Thr Leu Glu Glu Phe Gln His Leu Leu 180 185 190 Pro Lys Met LysVal Leu Leu Pro Ala Leu Gln Lys Glu Val Leu Phe 195 200 205 Ser Lys AsnAsp Pro Cys Ile Thr Ala Ser Glu Ser Pro Ala Glu Thr 210 215 220 Asn MetVal Trp Tyr Asp Trp Met Arg Pro Ser His Ala Gln Leu His 225 230 235 240Ser Asp Tyr Met Gln Pro Leu Thr Glu Ala Lys Ala Lys Ser Lys Asn 245 250255 Lys Val Arg Gly Val Gln Gln Leu Ile Gln Arg Leu Arg Leu Ile Lys 260265 270 Ser Pro Ala Glu Ile Glu Arg Met Gln Ile Ala Gly Lys Leu Thr Ser275 280 285 Gln Ala Phe Ile Glu Thr Met Phe Thr Ser Lys Ala Pro Val GluGlu 290 295 300 Ala Phe Leu Tyr Ala Lys Phe Glu Phe Glu Cys Arg Ala ArgGly Ala 305 310 315 320 Asp Ile Leu Ala Tyr Pro Pro Val Val Ala Gly GlyAsn Arg Ser Asn 325 330 335 Thr Leu His Tyr Val Lys Asn Asn Gln Leu IleLys Asp Gly Glu Met 340 345 350 Val Leu Leu Asp Gly Gly Cys Glu Ser SerCys Tyr Val Ser Asp Ile 355 360 365 Thr Arg Thr Trp Pro Val Asn Gly ArgPhe Thr Ala Pro Gln Ala Glu 370 375 380 Leu Tyr Glu Ala Val Leu Glu IleGln Arg Asp Cys Leu Ala Leu Cys 385 390 395 400 Phe Pro Gly Thr Ser LeuGlu Asn Ile Tyr Ser Met Met Leu Thr Leu 405 410 415 Ile Gly Gln Lys LeuLys Asp Leu Gly Ile Met Lys Asn Ile Lys Glu 420 425 430 Asn Asn Ala PheLys Ala Ala Arg Lys Tyr Cys Pro His His Val Gly 435 440 445 His Tyr LeuGly Met Asp Val His Asp Thr Pro Asp Met Pro Arg Ser 450 455 460 Leu ProLeu Gln Pro Gly Met Val Ile Thr Ile Glu Pro Gly Ile Tyr 465 470 475 480Ile Pro Glu Asp Asp Lys Asp Ala Pro Glu Lys Phe Arg Gly Leu Gly 485 490495 Val Arg Ile Glu Asp Asp Val Val Val Thr Gln Asp Ser Pro Leu Ile 500505 510 Leu Ser Ala Asp Cys Pro Lys Glu Met Asn Asp Ile Glu Gln Ile Cys515 520 525 Ser Gln Ala Ser 530 21 1287 DNA homo sapiens 21 atgtctctgatccagaagga agctcaaggg cagagtggga cagaccagac agtggttgtg 60 ctctccaaccctacatacta catgagcaac gatattccct atactttcca ccaagacaac 120 aatttcctgtacctatgtgg attccaagag cctgatagca ttcttgtcct tcagagcctc 180 cctggcaaacaattaccatc acacaaagcc atactttttg tgcctcggcg agatcccagt 240 cgagaactttgggatggtcc gcgatctggc actgatggag caatagctct aactggagta 300 gacgaagcctatacgctaga agaatttcaa catcttctac caaaaatgaa agctgagacg 360 aacatggtttggtatgactg gatgaggccc tcacatgcac agcttcactc tgactatatg 420 cagcccctgactgaggccaa agccaagagc aagaacaagg ttcggggtgt tcagcagctg 480 atacagcgcctccggctgat caagtctcct gcagaaattg aacgaatgca gattgctggg 540 aagctgacatcacaggcttt catagaaacc atgttcacca gtaaagcccc tgtggaagaa 600 gcctttctttatgctaagtt tgaatttgaa tgccgggctc gtggcgcaga cattttagcc 660 tatccacctgtggtggctgg tggtaatcgg tcaaacactt tgcactatgt gaaaaataat 720 caactcatcaaggatgggga aatggtgctt ctggatggag gttgtgagtc ttcctgctat 780 gtgagtgacatcacacgtac gtggccagtc aatggcaggt tcaccgcacc tcaggcagaa 840 ctctatgaagccgttctaga gatccaaaga gattgtttgg ccctctgctt ccctgggaca 900 agcttggagaacatctacag catgatgctg accctgatag gacagaagct taaagacttg 960 gggatcatgaagaacattaa ggaaaataat gccttcaagg ctgctcgaaa atactgtcct 1020 catcatgttggccactacct cgggatggat gtccatgaca ctccagacat gccccgttcc 1080 ctccctctgcagcctgggat ggtaatcaca attgagcccg gcatttatat tccagaggat 1140 gacaaagatgccccagagaa gtttcggggt cttggtgtac gaattgagga tgatgtagtg 1200 gtgactcaggactcacctct catcctttct gcagactgtc ccaaagagat gaatgacatt 1260 gaacagatatgcagccaggc ttcttga 1287 22 428 PRT homo sapiens 22 Met Ser Leu Ile GlnLys Glu Ala Gln Gly Gln Ser Gly Thr Asp Gln 1 5 10 15 Thr Val Val ValLeu Ser Asn Pro Thr Tyr Tyr Met Ser Asn Asp Ile 20 25 30 Pro Tyr Thr PheHis Gln Asp Asn Asn Phe Leu Tyr Leu Cys Gly Phe 35 40 45 Gln Glu Pro AspSer Ile Leu Val Leu Gln Ser Leu Pro Gly Lys Gln 50 55 60 Leu Pro Ser HisLys Ala Ile Leu Phe Val Pro Arg Arg Asp Pro Ser 65 70 75 80 Arg Glu LeuTrp Asp Gly Pro Arg Ser Gly Thr Asp Gly Ala Ile Ala 85 90 95 Leu Thr GlyVal Asp Glu Ala Tyr Thr Leu Glu Glu Phe Gln His Leu 100 105 110 Leu ProLys Met Lys Ala Glu Thr Asn Met Val Trp Tyr Asp Trp Met 115 120 125 ArgPro Ser His Ala Gln Leu His Ser Asp Tyr Met Gln Pro Leu Thr 130 135 140Glu Ala Lys Ala Lys Ser Lys Asn Lys Val Arg Gly Val Gln Gln Leu 145 150155 160 Ile Gln Arg Leu Arg Leu Ile Lys Ser Pro Ala Glu Ile Glu Arg Met165 170 175 Gln Ile Ala Gly Lys Leu Thr Ser Gln Ala Phe Ile Glu Thr MetPhe 180 185 190 Thr Ser Lys Ala Pro Val Glu Glu Ala Phe Leu Tyr Ala LysPhe Glu 195 200 205 Phe Glu Cys Arg Ala Arg Gly Ala Asp Ile Leu Ala TyrPro Pro Val 210 215 220 Val Ala Gly Gly Asn Arg Ser Asn Thr Leu His TyrVal Lys Asn Asn 225 230 235 240 Gln Leu Ile Lys Asp Gly Glu Met Val LeuLeu Asp Gly Gly Cys Glu 245 250 255 Ser Ser Cys Tyr Val Ser Asp Ile ThrArg Thr Trp Pro Val Asn Gly 260 265 270 Arg Phe Thr Ala Pro Gln Ala GluLeu Tyr Glu Ala Val Leu Glu Ile 275 280 285 Gln Arg Asp Cys Leu Ala LeuCys Phe Pro Gly Thr Ser Leu Glu Asn 290 295 300 Ile Tyr Ser Met Met LeuThr Leu Ile Gly Gln Lys Leu Lys Asp Leu 305 310 315 320 Gly Ile Met LysAsn Ile Lys Glu Asn Asn Ala Phe Lys Ala Ala Arg 325 330 335 Lys Tyr CysPro His His Val Gly His Tyr Leu Gly Met Asp Val His 340 345 350 Asp ThrPro Asp Met Pro Arg Ser Leu Pro Leu Gln Pro Gly Met Val 355 360 365 IleThr Ile Glu Pro Gly Ile Tyr Ile Pro Glu Asp Asp Lys Asp Ala 370 375 380Pro Glu Lys Phe Arg Gly Leu Gly Val Arg Ile Glu Asp Asp Val Val 385 390395 400 Val Thr Gln Asp Ser Pro Leu Ile Leu Ser Ala Asp Cys Pro Lys Glu405 410 415 Met Asn Asp Ile Glu Gln Ile Cys Ser Gln Ala Ser 420 425 231530 DNA homo sapiens 23 atgttgtgtt cacagcgaag gtactccctt cagcctgtcccagaaaggag gattccaaac 60 cgatacttag gccagcccag cccctttaca cacccacacctcctcagacc aggggaggta 120 actccaggac tatctcaggt ggaatatgca cttcgcagacacaaactaat gtctctgatc 180 cagaaggaag ctcaagggca gagtgggaca gaccagacagtggttgtgct ctccaaccct 240 acatactaca tgagcaacga tattccctat actttccaccaagacaacaa tttcctgtac 300 ctatgtggat tccaagagcc tgatagcatt cttgtccttcagagcctccc tggcaaacaa 360 ttaccatcac acaaagccat actttttgtg cctcggcgagatcccagtcg agaactttgg 420 gatggtccgc gatctggcac tgatggagca atagctctaactggagtaga cgaagcctat 480 acgctagaag aatttcaaca tcttctacca aaaatgaaagtgctcttgcc agctcttcaa 540 aaggaggtac tgttctccaa gaacgatcca tgcatcacagcatcagaatc acctgctgag 600 acgaacatgg tttggtatga ctggatgagg ccctcacatgcacagcttca ctctgactat 660 atgcagcccc tgactgaggc caaagccaag agcaagaacaaggttcgggg tgttcagcag 720 ctgatacagc gcctccggct gatcaagtct cctgcagaaattgaacgaat gcagattgct 780 gggaagctga catcacaggc tttcatagaa accatgttcaccagtaaagc ccctgtggaa 840 gaagcctttc tttatgctaa gtttgaattt gaatgccgggctcgtggcgc agacatttta 900 gcctatccac ctgtggtggc tggtggtaat cggtcaaacactttgcacta tgtgaaaaat 960 aatcaactca tcaaggatgg ggaaatggtg cttctggatggaggttgtga gtcttcctgc 1020 tatgtgagtg acatcacacg tacgtggcca gtcaatggcaggttcaccgc acctcaggca 1080 gaactctatg aagccgttct agagatccaa agagattgtttggccctctg cttccctggg 1140 acaagcttgg agaacatcta cagcatgatg ctgaccctgataggacagaa gcttaaagac 1200 ttggggatca tgaagaacat taaggaaaat aatgccttcaaggctgctcg aaaatactgt 1260 cctcatcatg ttggccacta cctcgggatg gatgtccatgacactccaga catgccccgt 1320 tccctccctc tgcagcctgg gatggtaatc acaattgagcccggcattta tattccagag 1380 gatgacaaag atgccccaga gaagtttcgg ggtcttggtgtacgaattga ggatgatgta 1440 gtggtgactc aggactcacc tctcatcctt tctgcagactgtcccaaaga gatgaatgac 1500 attgaacaga tatgcagcca ggcttcttga 1530 24 509PRT homo sapiens 24 Met Leu Cys Ser Gln Arg Arg Tyr Ser Leu Gln Pro ValPro Glu Arg 1 5 10 15 Arg Ile Pro Asn Arg Tyr Leu Gly Gln Pro Ser ProPhe Thr His Pro 20 25 30 His Leu Leu Arg Pro Gly Glu Val Thr Pro Gly LeuSer Gln Val Glu 35 40 45 Tyr Ala Leu Arg Arg His Lys Leu Met Ser Leu IleGln Lys Glu Ala 50 55 60 Gln Gly Gln Ser Gly Thr Asp Gln Thr Val Val ValLeu Ser Asn Pro 65 70 75 80 Thr Tyr Tyr Met Ser Asn Asp Ile Pro Tyr ThrPhe His Gln Asp Asn 85 90 95 Asn Phe Leu Tyr Leu Cys Gly Phe Gln Glu ProAsp Ser Ile Leu Val 100 105 110 Leu Gln Ser Leu Pro Gly Lys Gln Leu ProSer His Lys Ala Ile Leu 115 120 125 Phe Val Pro Arg Arg Asp Pro Ser ArgGlu Leu Trp Asp Gly Pro Arg 130 135 140 Ser Gly Thr Asp Gly Ala Ile AlaLeu Thr Gly Val Asp Glu Ala Tyr 145 150 155 160 Thr Leu Glu Glu Phe GlnHis Leu Leu Pro Lys Met Lys Val Leu Leu 165 170 175 Pro Ala Leu Gln LysGlu Val Leu Phe Ser Lys Asn Asp Pro Cys Ile 180 185 190 Thr Ala Ser GluSer Pro Ala Glu Thr Asn Met Val Trp Tyr Asp Trp 195 200 205 Met Arg ProSer His Ala Gln Leu His Ser Asp Tyr Met Gln Pro Leu 210 215 220 Thr GluAla Lys Ala Lys Ser Lys Asn Lys Val Arg Gly Val Gln Gln 225 230 235 240Leu Ile Gln Arg Leu Arg Leu Ile Lys Ser Pro Ala Glu Ile Glu Arg 245 250255 Met Gln Ile Ala Gly Lys Leu Thr Ser Gln Ala Phe Ile Glu Thr Met 260265 270 Phe Thr Ser Lys Ala Pro Val Glu Glu Ala Phe Leu Tyr Ala Lys Phe275 280 285 Glu Phe Glu Cys Arg Ala Arg Gly Ala Asp Ile Leu Ala Tyr ProPro 290 295 300 Val Val Ala Gly Gly Asn Arg Ser Asn Thr Leu His Tyr ValLys Asn 305 310 315 320 Asn Gln Leu Ile Lys Asp Gly Glu Met Val Leu LeuAsp Gly Gly Cys 325 330 335 Glu Ser Ser Cys Tyr Val Ser Asp Ile Thr ArgThr Trp Pro Val Asn 340 345 350 Gly Arg Phe Thr Ala Pro Gln Ala Glu LeuTyr Glu Ala Val Leu Glu 355 360 365 Ile Gln Arg Asp Cys Leu Ala Leu CysPhe Pro Gly Thr Ser Leu Glu 370 375 380 Asn Ile Tyr Ser Met Met Leu ThrLeu Ile Gly Gln Lys Leu Lys Asp 385 390 395 400 Leu Gly Ile Met Lys AsnIle Lys Glu Asn Asn Ala Phe Lys Ala Ala 405 410 415 Arg Lys Tyr Cys ProHis His Val Gly His Tyr Leu Gly Met Asp Val 420 425 430 His Asp Thr ProAsp Met Pro Arg Ser Leu Pro Leu Gln Pro Gly Met 435 440 445 Val Ile ThrIle Glu Pro Gly Ile Tyr Ile Pro Glu Asp Asp Lys Asp 450 455 460 Ala ProGlu Lys Phe Arg Gly Leu Gly Val Arg Ile Glu Asp Asp Val 465 470 475 480Val Val Thr Gln Asp Ser Pro Leu Ile Leu Ser Ala Asp Cys Pro Lys 485 490495 Glu Met Asn Asp Ile Glu Gln Ile Cys Ser Gln Ala Ser 500 505 25 1455DNA homo sapiens 25 atgttgtgtt cacagcgaag gtactccctt cagcctgtcccagaaaggag gattccaaac 60 cgatacttag gccagcccag cccctttaca cacccacacctcctcagacc aggggaggta 120 actccaggac tatctcaggt ggaatatgca cttcgcagacacaaactaat gtctctgatc 180 cagaaggaag ctcaagggca gagtgggaca gaccagacagtggttgtgct ctccaaccct 240 acatactaca tgagcaacga tattccctat actttccaccaagacaacaa tttcctgtac 300 ctatgtggat tccaagagcc tgatagcatt cttgtccttcagagcctccc tggcaaacaa 360 ttaccatcac acaaagccat actttttgtg cctcggcgagatcccagtcg agaactttgg 420 gatggtccgc gatctggcac tgatggagca atagctctaactggagtaga cgaagcctat 480 acgctagaag aatttcaaca tcttctacca aaaatgaaagctgagacgaa catggtttgg 540 tatgactgga tgaggccctc acatgcacag cttcactctgactatatgca gcccctgact 600 gaggccaaag ccaagagcaa gaacaaggtt cggggtgttcagcagctgat acagcgcctc 660 cggctgatca agtctcctgc agaaattgaa cgaatgcagattgctgggaa gctgacatca 720 caggctttca tagaaaccat gttcaccagt aaagcccctgtggaagaagc ctttctttat 780 gctaagtttg aatttgaatg ccgggctcgt ggcgcagacattttagccta tccacctgtg 840 gtggctggtg gtaatcggtc aaacactttg cactatgtgaaaaataatca actcatcaag 900 gatggggaaa tggtgcttct ggatggaggt tgtgagtcttcctgctatgt gagtgacatc 960 acacgtacgt ggccagtcaa tggcaggttc accgcacctcaggcagaact ctatgaagcc 1020 gttctagaga tccaaagaga ttgtttggcc ctctgcttccctgggacaag cttggagaac 1080 atctacagca tgatgctgac cctgatagga cagaagcttaaagacttggg gatcatgaag 1140 aacattaagg aaaataatgc cttcaaggct gctcgaaaatactgtcctca tcatgttggc 1200 cactacctcg ggatggatgt ccatgacact ccagacatgccccgttccct ccctctgcag 1260 cctgggatgg taatcacaat tgagcccggc atttatattccagaggatga caaagatgcc 1320 ccagagaagt ttcggggtct tggtgtacga attgaggatgatgtagtggt gactcaggac 1380 tcacctctca tcctttctgc agactgtccc aaagagatgaatgacattga acagatatgc 1440 agccaggctt cttga 1455 26 484 PRT homo sapiens26 Met Leu Cys Ser Gln Arg Arg Tyr Ser Leu Gln Pro Val Pro Glu Arg 1 510 15 Arg Ile Pro Asn Arg Tyr Leu Gly Gln Pro Ser Pro Phe Thr His Pro 2025 30 His Leu Leu Arg Pro Gly Glu Val Thr Pro Gly Leu Ser Gln Val Glu 3540 45 Tyr Ala Leu Arg Arg His Lys Leu Met Ser Leu Ile Gln Lys Glu Ala 5055 60 Gln Gly Gln Ser Gly Thr Asp Gln Thr Val Val Val Leu Ser Asn Pro 6570 75 80 Thr Tyr Tyr Met Ser Asn Asp Ile Pro Tyr Thr Phe His Gln Asp Asn85 90 95 Asn Phe Leu Tyr Leu Cys Gly Phe Gln Glu Pro Asp Ser Ile Leu Val100 105 110 Leu Gln Ser Leu Pro Gly Lys Gln Leu Pro Ser His Lys Ala IleLeu 115 120 125 Phe Val Pro Arg Arg Asp Pro Ser Arg Glu Leu Trp Asp GlyPro Arg 130 135 140 Ser Gly Thr Asp Gly Ala Ile Ala Leu Thr Gly Val AspGlu Ala Tyr 145 150 155 160 Thr Leu Glu Glu Phe Gln His Leu Leu Pro LysMet Lys Ala Glu Thr 165 170 175 Asn Met Val Trp Tyr Asp Trp Met Arg ProSer His Ala Gln Leu His 180 185 190 Ser Asp Tyr Met Gln Pro Leu Thr GluAla Lys Ala Lys Ser Lys Asn 195 200 205 Lys Val Arg Gly Val Gln Gln LeuIle Gln Arg Leu Arg Leu Ile Lys 210 215 220 Ser Pro Ala Glu Ile Glu ArgMet Gln Ile Ala Gly Lys Leu Thr Ser 225 230 235 240 Gln Ala Phe Ile GluThr Met Phe Thr Ser Lys Ala Pro Val Glu Glu 245 250 255 Ala Phe Leu TyrAla Lys Phe Glu Phe Glu Cys Arg Ala Arg Gly Ala 260 265 270 Asp Ile LeuAla Tyr Pro Pro Val Val Ala Gly Gly Asn Arg Ser Asn 275 280 285 Thr LeuHis Tyr Val Lys Asn Asn Gln Leu Ile Lys Asp Gly Glu Met 290 295 300 ValLeu Leu Asp Gly Gly Cys Glu Ser Ser Cys Tyr Val Ser Asp Ile 305 310 315320 Thr Arg Thr Trp Pro Val Asn Gly Arg Phe Thr Ala Pro Gln Ala Glu 325330 335 Leu Tyr Glu Ala Val Leu Glu Ile Gln Arg Asp Cys Leu Ala Leu Cys340 345 350 Phe Pro Gly Thr Ser Leu Glu Asn Ile Tyr Ser Met Met Leu ThrLeu 355 360 365 Ile Gly Gln Lys Leu Lys Asp Leu Gly Ile Met Lys Asn IleLys Glu 370 375 380 Asn Asn Ala Phe Lys Ala Ala Arg Lys Tyr Cys Pro HisHis Val Gly 385 390 395 400 His Tyr Leu Gly Met Asp Val His Asp Thr ProAsp Met Pro Arg Ser 405 410 415 Leu Pro Leu Gln Pro Gly Met Val Ile ThrIle Glu Pro Gly Ile Tyr 420 425 430 Ile Pro Glu Asp Asp Lys Asp Ala ProGlu Lys Phe Arg Gly Leu Gly 435 440 445 Val Arg Ile Glu Asp Asp Val ValVal Thr Gln Asp Ser Pro Leu Ile 450 455 460 Leu Ser Ala Asp Cys Pro LysGlu Met Asn Asp Ile Glu Gln Ile Cys 465 470 475 480 Ser Gln Ala Ser 273208 DNA homo sapiens 27 gcggccctgc aggcggttgc gttccccgtc gttaccctctttctcttccc gacgcgtgag 60 ttaggccgta atgccttggc tgctctcagc ccccaagctggttcccgctg tagcaaacgt 120 ccgcggcctc tcagtcctga atcctctgga ctgtttcccctgtatgtttc cctggaagct 180 tcaggcagtg cctcataagc caatggaatc tgttgctaatagccacagca tatcccttgc 240 ataatatgac ctctagatta ctgcgcctta attgcttcccagctcttcta tgctttggtt 300 tagaaaaatg aagtactgac ttacgggtga agaaagtattcaaacagttg acatatttat 360 ttcagtcaag aaacagttca gagggagata caaacaagtaacttagttac aatataatag 420 ttatgatgag aggaagtact ggatgctaaa caattatatgagagacagct caggctgggg 480 gtgtcaatga aagcctcttg gaggaagtag cctgatatgttaactttctg catgccagtg 540 aagacactat gtgtgcatga gtacgtgtgc acgagcgtgcatgtggagaa ggtgcaggag 600 gagagaaaga gaaatcacca atgcaacagc agcctactccaccagtgggt tagtgctgct 660 ggagggagat gaaaagatta ggaaggatgt atgttgtgttcacagcgaag gtactccctt 720 cagcctgtcc cagaaaggag gattccaaac cgatacttaggccagcccag cccctttaca 780 cacccacacc tcctcagacc agactcgaat tcctgctgggaagtcggctg aaactaagga 840 aatgcagctc accactgaaa cccacaagaa atcagagtttttcaaagctg taaggggagg 900 taactccagg actatctcag gtggaatatg cacttcgcagacacaaacta atgtctctga 960 tccagaagga agctcaaggg cagagtggga cagaccagacagtggttgtg ctctccaacc 1020 ctacatacta catgagcaac gatattccct atactttccaccaagacaac aatttcctgt 1080 acctatgtgg attccaagag cctgatagca ttcttgtccttcagagcctc cctggcaaac 1140 aattaccatc acacaaagcc atactttttg tgcctcggcgagatcccagt cgagaacttt 1200 gggatggtcc gcgatctggc actgatggag caatagctctaactggagta gacgaagcct 1260 atacgctaga agaatttcaa catcttctac caaaaatgaaagtgctcttg ccagctcttc 1320 aaaaggaggt actgttctcc aagaacgatc catgcatcacagcatcagaa tcacctgctg 1380 agacgaacat ggtttggtat gactggatga ggccctcacatgcacagctt cactctgact 1440 atatgcagcc cctgactgag gccaaagcca agagcaagaacaaggttcgg ggtgttcagc 1500 agctgataca gcgcctccgg ctgatcaagt ctcctgcagaaattgaacga atgcagattg 1560 ctgggaagct gacatcacag gtatgattcc tattgaaaagttttttccag ccgggcgcgg 1620 tggctcacgc ctgtaatcca agcactttgg gaggccgaggcaggtggatc atgaggtcag 1680 gagatcgaga ccatcctggc taacatggtg aaaccccgtctctactaaaa aaacataaaa 1740 aattagccgg gcatggtggc gggctcctgt agtcccagctactcggtagg ctgaggcagg 1800 agaatggtgt gaacccggga ggcagagctt gcagtgagccgagatcgggc cactgcactc 1860 cagcctggcg acagacgaga ttcatcttaa aaaaaaaaaaaaaaaaaact ttcatagaaa 1920 ccatgttcac cagtaaagcc cctgtggaag aagcctttctttatgctaag tttgaatttg 1980 aatgccgggc tcgtggcgca gacattttag cctatccacctgtggtggct ggtggtaatc 2040 ggtcaaacac tttgcactat gtgaaaaata atcaactcatcaaggatggg gaaatggtgc 2100 ttctggatgg aggttgtgag tcttcctgct atgtgagtgacatcacacgt acgtggccag 2160 tcaatggcag gttcaccgca cctcaggcag aactctatgaagccgttcta gagatccaaa 2220 gagattgttt ggccctctgc ttccctggga caagcttggagaacatctac agcatgatgc 2280 tgaccctgat aggacagaag cttaaagact tggggatcatgaagaacatt aaggaaaata 2340 atgccttcaa ggctgctcga aaatactgtc ctcatcatgttggccactac ctcgggatgg 2400 atgtccatga cactccagac atgccccgtt ccctccctctgcagcctggg atggtaatca 2460 caattgagcc cggcatttat attccagagg atgacaaagatgccccagag aagtttcggg 2520 gtcttggtgt acgaattgag gatgatgtag tggtgactcaggactcacct ctcatccttt 2580 ctgcagactg tcccaaagag atgaatgaca ttgaacagatatgcagccag gcttcttgac 2640 cttcactgcg gcccacatgc acctcaggtt caaaatgggtgtcttctggc agccctgcac 2700 gtgtgctttc tgagtgtctc tgtgtgtgca ttaatatatgcattccattt gggagcataa 2760 aaaaaaaaaa aaaaatggaa tgcagtagcc ctctgggcctgggatattgt ggttgataac 2820 tgtgccatct gcaggaacca cattatggat ctttgcatagaatgtcaagc taaccaggcg 2880 tccgctactt cagaagagtg tactgtcgca tggggagtctgtaaccatgc ttttcacttc 2940 cactgcatct ctcgctggct caaaacacga caggtgtgtccattggacaa cagagagtgg 3000 gaattccaaa agtatgggca ctaggaaaag acttcttccatcaagcttaa ttgttttgtt 3060 attcatttaa tgactttccc tgctgttacc taattacaaattggatggaa ctgtgttttt 3120 ttctgctttg ttttttcagt ttgctgtttc tgtagccatattggattctg tgtcaaataa 3180 agtccagttg gattctggaa aaaaaaaa 3208

What is claimed is:
 1. An isolated nucleic acid molecule comprising atleast 24 contiguous bases of nucleotide sequence first disclosed in SEQID NO:
 1. 2. An isolated nucleic acid molecule comprising a nucleotidesequence that: (a) encodes the amino acid sequence shown in SEQ ID NO:2; and (b) hybridizes under stringent conditions to the nucleotidesequence of SEQ ID NO: 1 or the complement thereof.
 3. An isolatednucleic acid molecule encoding the amino acid sequence described in SEQID NO:
 20. 4. An isolated nucleic acid molecule encoding the amino acidsequence described in SEQ ID NO:
 24. 5. An isolated nucleic acidmolecule encoding the amino acid sequence described in SEQ ID NO: 26.